FCE

Varicella-Zoster Virus (VZV)

1. causes chickenpox-- and herpes zoster (shingles)

Bacillus anthracis

Anthrax

Vaccinia virus

COW POX Vaccinia virus (VACV or VV) is a large, complex, enveloped virus belonging to the poxvirus family.[2] It has a linear, double-stranded DNA genomeapproximately 190 kbp in length, which encodes approximately 250 genes. The dimensions of the virion are roughly 360 × 270 × 250 nm, with a mass of approximately 5-10 fg.[3] Smallpox was the first disease to be widely prevented by vaccination, due to pioneering work by the English physician and scientist Edward Jenner, in the eighteenth century, using cowpox virus. Vaccinia virus is the active constituent of the vaccine that eradicated smallpox, making it the first human disease to be eradicated. This endeavour was carried out by the World Health Organization under the Smallpox Eradication Program. Following the eradication of smallpox, scientists study vaccinia virus to use as a tool for delivering genes into biological tissues (gene therapy and genetic engineering) and because of concerns about smallpox being used as an agent for bioterrorism.

Rickettsia prowazekii Dz? Transmission? Tx?

Causes epidemic typhus Transmission via human body louse Tx: TCN

Salmonella typhi

Causes typhoid fever: diarrhea, HA, rose spots on abdomen. Can remain in gallbladder chronically.

Pasteurella multocida Disease? Transmission?

Causes: Cellulitis Transmission: Animal bit; cats, dogs

Coxsackie A and B viruses

Coxsackie B virusCoxsackie B4 virusVirus classificationGroup:Group IV ((+)ssRNA)Order:unassignedFamily:PicornaviridaeGenus:EnterovirusSpecies:Enterovirus BSubtype Coxsackie B virus Coxsackie B is a group of six serotypes of Coxsackievirus, a pathogenic enterovirus, that trigger illness ranging from gastrointestinal distress to full-fledged pericarditis and myocarditis (Coxsackievirus-induced cardiomyopathy).[1] The genome of Coxsackie B virus consists of approximately 7400 base pairs.[2] Contents 1Geographic distribution 2Symptoms 3Diagnosis 4Diabetes 5Treatment and prevention 6Persistent Coxsackie B virus (non-cytolytic infection) 7References The various members of the Coxsackie B group were discovered almost entirely in the United States, appearing originally in Connecticut, Ohio, New York, and Kentucky, although a sixth member of the group has been found in the Philippines.[1] However, all six serotypes have a global distribution and are a relatively common cause of gastrointestinal upset. The name reflects the first isolation from Coxsackie, New York. Symptoms of infection with viruses in the Coxsackie B grouping include fever, headache, sore throat, gastrointestinal distress, extreme fatigue as well as chest and muscle pain. Can also lead to spasms in arms and legs. This presentation is known as pleurodynia or Bornholm disease in many areas. Sufferers of chest pain should see a doctor immediately—in some cases, viruses in the Coxsackie B family progress to myocarditis or pericarditis, which can result in permanent heart damage or death. Coxsackie B virus infection may also induce aseptic meningitis. As a group, they are the most common cause of unexpected sudden death, and may account for up to 50% of such cases.[3] The incubation period for the Coxsackie B viruses ranges from 2 to 6 days, and illness may last for up to 6 months in extreme cases, but may resolve as quickly as two days. Infection usually occurs between the months of May and June but do not show symptoms until October in temperate Northern Hemisphere regions. People should ideally spend 1 month resting during the height of infection. Another cause of this virus is from a dirty wound from an accident.[1] Enterovirus infection is diagnosed mainly via serological tests such as ELISA[4] and from cell culture.[1] Because the same level and type of care is given regardless of type of Coxsackie B infection, it is mostly unnecessary for treatment purposes to diagnose which virus is causing the symptoms in question, though it may be epidemiologically useful. Main article: Coxsackie B4 virus The B4 strain of Coxsackie viruses was suggested to be a possible cause of Diabetes mellitus type 1.[5] More recent research implicates strains B1, A4, A2 and A16 in the destruction of beta cells,[6][7] with some suggestion that strains B3 and B6 may have protective effects via immunological cross-protection. As of 2008, there is no well-accepted treatment for the Coxsackie B group of viruses.[1] Palliative care is available, however, and patients suffering chest pain or stiffness of the neck should be examined for signs of cardiac or central nervous system involvement, respectively. Some measure of prevention can usually be achieved by basic sanitation on the part of food-service workers, though the viruses are highly contagious. Care should be taken in washing ones hands and in cleaning the body after swimming. In the event of Coxsackie-induced myocarditis or pericarditis, antiinflammatories can be given to reduce damage to the heart muscle. Enteroviruses are usually only capable of acute infections that are rapidly cleared by the adaptive immune response.[8][9] However mutations which enterovirus B serotypes such as coxsackievirus B and echovirus acquire in the host during the acute phase can transform these viruses into the non-cytolytic form (also known as non-cytopathic or defective enterovirus). This form is a mutated quasispecies[8] of enterovirus which is capable of causing persistent infection in human tissues, and such infections have been found in chronic myocarditis or dilated cardiomyopathy.[10][8] In these persistent infections, viral RNA is present at very low levels and some researchers believe it is just a fading remnant of the acute infection[9] although others think it may have pathological effects.[11]

Creutzfeldt-Jakob disease

Creutzfeldt-Jakob disease (CJD), also known as classic Creutzfeldt-Jakob disease, is a fatal degenerative brain disorder.[4][1] Early symptoms include memory problems, behavioral changes, poor coordination, and visual disturbances.[4] Later symptoms include dementia, involuntary movements, blindness, weakness, and coma.[4] About 70% of people die within a year of diagnosis.[4] CJD is caused by a protein known as a prion.[5] Infectious prions are misfolded proteins that can cause normally folded proteins to become misfolded.[4] About 85% occur spontaneously, while about 7.5% of cases are inherited from a person's parents in an autosomal dominantmanner.[4][6] Exposure to brain or spinal tissue from an infected person may also result in spread.[4] There is no evidence that it can spread between people via normal contact or blood transfusions.[4] Diagnosis involves ruling out other potential causes.[4] An electroencephalogram, spinal tap, or magnetic resonance imaging may support the diagnosis.[4] There is no specific treatment for CJD.[4] Opioids may be used to help with pain, while clonazepam or sodium valproate may help with involuntary movements.[4] CJD affects about one per million people per year.[4] Onset is typically around 60 years of age.[4] The condition was first described in 1920.[4] It is classified as a type of transmissible spongiform encephalopathy.[7] Inherited CJD accounts for about 10% of prion disease cases.[6] CJD is different from bovine spongiform encephalopathy (mad cow disease) and variant Creutzfeldt-Jakob disease (vCJD). The first symptom of CJD is usually rapidly progressive dementia, leading to memory loss, personality changes, and hallucinations. Myoclonus(jerky movements) typically occurs in 90% of cases, but may be absent at initial onset.[9] Other frequently occurring features include anxiety, depression, paranoia, obsessive-compulsive symptoms, and psychosis.[10] This is accompanied by physical problems such as speechimpairment, balance and coordination dysfunction (ataxia), changes in gait, and rigid posture. In most people with CJD, these symptoms are accompanied by involuntary movements. The duration of the disease varies greatly, but sporadic (non-inherited) CJD can be fatal within months or even weeks.[11] Most victims die six months after initial symptoms appear, often of pneumonia due to impaired coughing reflexes. About 15% of people with CJD survive for two or more years.[12] The symptoms of CJD are caused by the progressive death of the brain's nerve cells, which are associated with the build-up of abnormal prion proteins forming in the brain. When brain tissue from a person with CJD is examined under a microscope, many tiny holes can be seen where the nerve cells have died. Parts of the brain may resemble a sponge where the prion were infecting the areas of the brain.

Cryptococcus neoformans

Cryptococcus neoformans is an encapsulated yeast[1] and an obligate aerobe[2] that can live in both plants and animals. Its teleomorph is Filobasidiella neoformans, a filamentous fungus belonging to the class Tremellomycetes. It is often found in bird excrement. Cryptococcus neoformans is an encapsulated fungal organism and it can cause disease in apparently immunocompetent, as well as immunocompromised, hosts.[3] Contents 1Classification 2Characteristics 3Pathology 4Serious complications 5Treatment 6References 7External links Cryptococcus neoformans has undergone numerous nomenclature revisions since its first description in 1894. For instance, it once contained two varieties(var.): C. neoformans var. neoformans and C. neoformans var. grubii. A third variety, C. neoformans var. gattii, was defined as a distinct species, Cryptococcus gattii. The most recent classification system divides organisms into seven species.[4] C. neoformans refers to C. neoformans var. grubii. A new species name, Cryptococcus deneoformans, is used for the former C. neoformans var. neoformans. C. gattii is divided into five species. C. neoformans stained by Gram stain This section may be too technical for most readers to understand. Please help improve it to make it understandable to non-experts, without removing the technical details. (February 2020) (Learn how and when to remove this template message) C. neoformans grows as a yeast (unicellular) and replicates by budding. It makes hyphae during mating, and eventually creates basidiospores at the end of the hyphae before producing spores. Under host-relevant conditions, including low glucose, serum, 5% carbon dioxide, and low iron, among others, the cells produce a characteristic polysaccharide capsule.[5] The recognition of C. neoformans in Gram-stained smears of purulent exudates may be hampered by the presence of the large gelatinous capsule which apparently prevents definitive staining of the yeast-like cells. In such stained preparations, it may appear either as round cells with Gram-positive granular inclusions impressed upon a pale lavender cytoplasmic background or as Gram-negative lipoid bodies.[6] When grown as a yeast, C. neoformans has a prominent capsule composed mostly of polysaccharides. Under the microscope, the India ink stain is used for easy visualization of the capsule in cerebral spinal fluid.[7] The particles of ink pigment do not enter the capsule that surrounds the spherical yeast cell, resulting in a zone of clearance or "halo" around the cells. This allows for quick and easy identification of C. neoformans. Unusual morphological forms are rarely seen.[8] For identification in tissue, mucicarmine stain provides specific staining of polysaccharide cell wall in C. neoformans. Cryptococcal antigen from cerebrospinal fluid is thought to be the best test for diagnosis of cryptococcal meningitis in terms of sensitivity, though it might be unreliable in HIV-positive patients.[9] The first genome sequence for a strain of C. neoformans (var. neoformans; now C. deneoformans) was published in 2005.[10] Studies suggest that colonies of C. neoformans and related fungi growing on the ruins of the melted down reactor of the Chernobyl nuclear power plant may be able to use the energy of radiationfor "radiotrophic" growth.[11] Infection with C. neoformans is termed cryptococcosis. Most infections with C. neoformans occur in the lungs.[12] However, fungal meningitis and encephalitis, especially as a secondary infection for AIDS patients, are often caused by C. neoformans, making it a particularly dangerous fungus. Infections with this fungus are rare in those with fully functioning immune systems.[13] So, C. neoformans is sometimes referred to as an opportunistic fungus.[13] It is a facultative intracellular pathogen[14] that can utilize host phagocytes to spread within the body.[15][16] Cryptococcus neoformans was the first intracellular pathogen for which the non-lytic escape process termed vomocytosis was observed.[17][18] It has been speculated that this ability to manipulate host cells results from environmental selective pressure by amoebae, a hypothesis first proposed by Arturo Casadevall under the term "accidental virulence".[19] In human infection, C. neoformans is spread by inhalation of aerosolized basidiospores, and can disseminate to the central nervous system, where it can cause meningoencephalitis.[20] In the lungs, C. neoformans cells are phagocytosed by alveolar macrophages.[21] Macrophages produce oxidative and nitrosative agents, creating a hostile environment, to kill invading pathogens.[22]However, some C. neoformans cells can survive intracellularly in macrophages.[21] Intracellular survival appears to be the basis for latency, disseminated disease, and resistance to eradication by antifungal agents. One mechanism by which C. neoformans survives the hostile intracellular environment of the macrophage involves upregulation of expression of genes involved in responses to oxidative stress.[21] Traversal of the blood-brain barrier by C. neoformans plays a key role in meningitis pathogenesis.[23] However, precise mechanisms by which it passes the blood-brain barrier are still unknown; one recent study in rats suggested an important role of secreted serine proteases.[24] The metalloprotease Mpr1 has been demonstrated to be critical in blood-brain barrier penetration.[25] Meiosis (sexual reproduction), another possible survival factor for intracellular C. neoformans The vast majority of environmental and clinical isolates of C. neoformans are mating type alpha. Filaments of mating type alpha have haploid nuclei ordinarily, but these can undergo a process of diploidization (perhaps by endoduplication or stimulated nuclear fusion) to form diploid cells termed blastospores. The diploid nuclei of blastospores are able to undergo meiosis, including recombination, to form haploid basidiospores that can then be dispersed.[26] This process is referred to as monokaryotic fruiting. Required for this process is a gene designated dmc1, a conserved homologue of genes recA in bacteria, and rad51 in eukaryotes (see articles recA and rad51). Dmc1 mediates homologous chromosome pairing during meiosis and repair of double-strand breaks in DNA.[27] One benefit of meiosis in C. neoformans could be to promote DNA repair in the DNA-damaging environment caused by the oxidative and nitrosative agents produced in macrophages.[26]Thus, C. neoformans can undergo a meiotic process, monokaryotic fruiting, that may promote recombinational repair in the oxidative, DNA-damaging environment of the host macrophage, and this may contribute to its virulence. Infection starts in lungs, disseminates via blood to meninges and then to other parts of the body. Capsule inhibits phagocytosis. Can cause a systemic infection, including fatal meningitis known as meningoencephalitis in normal, diabetic and immunocompromised hosts. The infection from C. neoformans in the brain can be fatal if untreated. CNS (central nervous system) infection may also be present as a brain abscess known as cryptococcomas, subdural effusion, dementia, isolated cranial nerve lesion, spinal cord lesion, and ischemic stroke. If cryptococcal meningitis occurs, mortality rate is between 10-30%.[28] C. neoformans seen in the lung of a patient with AIDS: The inner capsule of the organism stains red in this photomicrograph. Cryptococcosis that does not affect the central nervous system can be treated with fluconazole alone. Cryptococcal meningitis should be treated for two weeks with intravenous amphotericin B 0.7-1.0 mg/kg/day and oral flucytosine 100 mg/kg/day (or intravenous flucytosine 75 mg/kg/day if the patient is unable to swallow). This should then be followed by oral fluconazole 400-800 mg daily for ten weeks[29] and then 200 mg daily for at least one year and until the patient's CD4 count is above 200 cells/mcl.[30][31] Flucytosine is a generic, off-patent medicine. However, a market failure exists, with a two-week cost of flucytosine therapy being about $10,000. As a result, flucytosine is currently universally unavailable in low- and middle-income countries. In 1970, flucytosine was available in Africa.[32] Intravenous ambisome 4 (mg/kg)/day may be used but is not superior; its main use is in patients who do not tolerate amphotericin B. The dose of 200 mg/kg/day for flucytosine is not more effective, is associated with more side effects and should not be used. In Africa, oral fluconazole at a rate of 200 mg daily is often used. However, this does not result in cure, because it merely suppresses the fungus and does not kill it; viable fungus can continue to be grown from cerebrospinal fluid of patients not having taken fluconazole for many months. An increased dose of 400 mg daily does not improve outcomes,[33] but prospective studies from Uganda and Malawi reported that higher doses of 1200 mg per day have more fungicidal activity.[34] The outcomes with fluconazole monotherapy have 30% worse survival than amphotericin-based therapies, in a recent systematic review

Chlamydia trachomatis

Doxycycline (+ ceftriaxone for gonorrhea coinfection), erythromycin eye drops (prophylaxis in infants)

Filovirus

Ebola

Hepatitis viruses

HAV - RNA picornovirus HBV - DNA hepadnavirus HCV - RNA flavivirus HDV - RNA delta virus HEV - RNA hepevirus -All RNA except HBV

Borrelia burgdorferi

Lyme disease

Lyssavirus

Lyssavirus (from the Greek λύσσα lyssa "rage, fury, rabies" and the Latin vīrus)[1][2] is a genus of RNA viruses in the family Rhabdoviridae, order Mononegavirales. Mammals, including humans, can serve as natural hosts.[3][4] The genus Lyssavirus includes the rabies virus traditionally associated with that disease. Contents 1Taxonomy 2Virology2.1Structure2.2Genome2.3Evolution 3Life cycle 4Testing 5Epidemiology 6See also 7References 8Further reading 9External links Genus Lyssavirus: species and their viruses[5][6]GenusSpeciesVirus (Abbreviation)LyssavirusAravan lyssavirusAravan virus (ARAV)Australian bat lyssavirusAustralian bat lyssavirus (ABLV)Bokeloh bat lyssavirusBokeloh bat lyssavirus (BBLV)Duvenhage lyssavirusDuvenhage virus (DUVV)European bat 1 lyssavirusEuropean bat lyssavirus 1 (EBLV-1)European bat 2 lyssavirusEuropean bat lyssavirus 2 (EBLV-2)Gannoruwa bat lyssavirusGannoruwa bat lyssavirus (GBLV)Ikoma lyssavirusIkoma lyssavirus (IKOV)Irkut lyssavirusIrkut virus (IRKV)Khujand lyssavirusKhujand virus (KHUV)Lagos bat lyssavirusLagos bat virus (LBV)Lleida bat lyssavirusLleida bat lyssavirus (LLEBV)Mokola lyssavirusMokola virus (MOKV)Rabies lyssavirus*Rabies virus (RABV)Shimoni bat lyssavirusShimoni bat virus (SHIBV)West Caucasian bat lyssavirusWest Caucasian bat virus (WCBV) Table legend: "*" denotes type species. There is a new proposed species of Lyssavirus called Lleida bat lyssavirus (LLEBV). It was found in a common bent-wing bat (Miniopterus schreibersii) in Spain. It does not belong to phylogroups I or II, and it seems to be more closely related to the WCBV and the IKOV.[7] Lyssavirions are enveloped, with bullet shaped geometries. These virions are about 75 nm wide and 180 nm long.[3] Lyssavirions have helical symmetry, so their infectious particles are approximately cylindrical in shape. This is typical of plant-infecting viruses. Virions of human-infecting viruses more commonly have cubic symmetry and take shapes approximating regular polyhedra. The structure consists of a spiked outer envelope, a middle region consisting of matrix protein M, and an inner ribonucleocapsid complex region, consisting of the genome associated with other proteins. Lyssavirus genomes consist of a negative-sense, single-stranded RNA molecule that encodes five viral proteins: polymerase L, matrix protein M, phosphoprotein P, nucleoprotein N, and glycoprotein G. Genomes are linear, around 11kb in length.[3] Based on recent phylogenetic evidence, lyssaviruses have been categorized into seven major species. In addition, five more species have recently been discovered: West Caucasian bat virus, Aravan virus, Khujand virus, Irkut virus and Shimoni bat virus.[8][9] The major species (genotypes) include: rabies virus (genotype 1); Lagos bat virus (genotype 2); Mokola virus (genotype 3); Duvenhage virus (genotype 4); European Bat lyssaviruses type 1 and 2 (genotypes 5 and 6); and Australian bat lyssavirus (genotype 7).[10] Based on the biological properties of the viruses, these species are further subdivided into phylogroups 1 and 2. Phylogroup 1 includes genotypes 1, 4, 5, 6, and 7, while phylogroup 2 includes genotypes 2 and 3. The nucleocapsid region of lyssavirus is fairly highly conserved from genotype to genotype across both phylogroups; experimental data have shown that the only lyssavirus strains used in vaccinations are those from the first species (i.e. classic rabies) leaving their efficacy for some non-rabies Lyssavirus diseases (e.g. Mokola virus) in question.[10] GenusStructureSymmetryCapsidGenomic arrangementGenomic segmentationLyssavirusBullet-shapedEnvelopedLinearMonopartite There are three phylogeographic groups of lyssaviruses: 1 -3.[11] Rabies belongs to group 1, along with Aravan lyssavirus, Australian bat lyssavirus, Bokeloh bat lyssavirus, Duvenhage virus, European bat lyssavirus 1 and 2, Gannoruwa bat lyssavirus, Irkut lyssavirus and Khujand lyssavirus. Members of group 2 include Lagos bat virus, Mokola virus and Shimoni bat virus. Members of group 3 include Ikoma lyssavirus and Lleida bat lyssavirus. Phyogenetic studies suggest that the original hosts of these viruses were bats.[12] The greater antigenic diversity of lyssaviruses from Africa has led to the assumption that Africa was the origin of these viruses. An examination of 153 viruses collected between 1956 and 2015 from various geographic locations has instead suggested a Palearctic origin (85% likelihood) for these viruses.[13] Date estimates (95% likelihood) for the most recent common ancestor were very broad - between 3,995 and 166,820 years before present - which suggests there is further work to be done in this area. Although bats evolved in the Palearctic,[14] their origins antedate that of the lyassaviruses by millions of years, which argues against their co-speciation. The evolution rate in the N gene in the Africa 2 lineage has been estimated to be 3.75×10−3 substitutions per site per year.[15] This rate is similar to that of other RNA viruses. Viral replication is cytoplasmic. Entry into the host cell is achieved by attachment of the viral G glycoproteins to host receptors, which mediates clathrin-mediated endocytosis. Replication follows the negative stranded RNA virus replication model. Negative stranded RNA virus transcription, using polymerase stuttering, is the method of transcription. The virus exits the host cell by budding and by tubule-guided viral movement. Wild mammals, especially bats and certain carnivores, serve as natural hosts. Transmission routes are typically via bite wounds.[3] GenusHost detailsTissue tropismEntry detailsRelease detailsReplication siteAssembly siteTransmissionLyssavirusbats, Crocidura shrews and certain carnivoresNeuronsClathrin-mediated endocytosisBuddingCytoplasmCytoplasmBite wounds As of 2018 the direct fluorescent antibody (DFA) test is still the gold standard to detect lyssavirus infection. Since the new millennium reverse transcription PCR (RT-PCR) tests have been developed for rabies but only been used as a confirmatory test. Real-time PCR-based tests which have higher sensitivity and objective diagnostic thresholds and allow samples to be stored at room temperature have been promising since 2005, but require a real-time PCR machine, skilled workers with experience in molecular diagnostics. In an international evaluation a single TaqManLN34 assay could detect Lyssavirus with high sensitivity (99.90%) across the genus and high specificity (99.68%) when compared to the DFA test. It will become the primary post-mortem rabies diagnostic test where possible.[16] Classic rabies virus, is prevalent throughout most of the world and can be carried by any warm blooded mammal. The other lyssaviruses have much less diversity in carriers. Only select hosts can carry each of these viral species. Also, these other species are particular only to a specific geographic area. Bats are known to be an animal vector for all identified lyssaviruses except the Mokola virus.[17]

Adenovirus

Name the DNA virus: • Linear dsDNA; naked; replicates in the nucleus

Hepadnavirus

Name the DNA virus: • Partially dsDNA circular; enveloped; virion-associated polymerases; has RNA intermediate; replicates in the nucleus

Paramyxovirus

ParamyxoviridaeTEM micrograph of a Mumps rubulavirusparticleVirus classification(unranked):VirusRealm:RiboviriaPhylum:NegarnaviricotaClass:MonjiviricetesOrder:MononegaviralesFamily:ParamyxoviridaeGeneraAquaparamyxovirusAvulavirusFerlavirusHenipavirusMorbillivirusRespirovirusRubulavirus Phylogenetic tree of paramyxoviruses Paramyxoviridae is a family of viruses in the order Mononegavirales. Vertebrates serve as natural hosts; no known plants serve as vectors.[1] Currently, 72 species are placed in this family, divided among 14 genera.[2][3] Diseases associated with this negative-sense, single-stranded RNA virus family include measles, mumps, and respiratory tract infections.[4][5] Contents 1Taxonomy1.1Notes 2Life cycle 3Physical structure 4Genome structure 5Proteins 6Pathogenic paramyxoviruses 7Diversity and evolution 8See also 9References 10External links Family Paramyxoviridae: genera, species, and their viruses[6]GenusSpeciesVirus (abbreviation)AquaparamyxovirusSalmon aquaparamyxovirus*Atlantic salmon paramyxovirus (AsaPV)AvulavirusAvian avulavirus 1*avian paramyxovirus 1 (APMV-1)Avian avulavirus 2avian paramyxovirus 2 (APMV-2)Avian avulavirus 3avian paramyxovirus 3 (APMV-3)Avian avulavirus 4avian paramyxovirus 4 (APMV-4)Avian avulavirus 5avian paramyxovirus 5 (APMV-5)Avian avulavirus 6avian paramyxovirus 6 (APMV-6)Avian avulavirus 7avian paramyxovirus 7 (APMV-7)Avian avulavirus 8avian paramyxovirus 8 (APMV-8)Avian avulavirus 9avian paramyxovirus 9 (APMV-9)Avian avulavirus 10avian paramyxovirus 10 (APMV-10)Avian avulavirus 11avian paramyxovirus 11 (APMV-11)Avian avulavirus 12avian paramyxovirus 12 (APMV-12)Avian avulavirus 13avian paramyxovirus 13 (APMV-13)FerlavirusReptilian ferlavirus*Fer-de-Lance virus (FDLV)HenipavirusCedar henipavirusCedar virus (CedV)Ghanaian bat henipavirusKumasi virus (KV)Hendra henipavirus*Hendra virus (HeV)Mojiang henipavirusMòjiāng virus (MojV)Nipah henipavirusNipah virus (NiV)MorbillivirusCanine morbilliviruscanine distemper virus (CDV)Cetacean morbilliviruscetacean morbillivirus (CeMV)Feline morbillivirusfeline morbillivirus (FeMV)Measles morbillivirus*measles virus (MeV)Small ruminant morbilliviruspeste-des-petits-ruminants virus (PPRV)Phocine morbillivirusphocine distemper virus (PDV)Rinderpest morbillivirusrinderpest virus (RPV)RespirovirusBovine respirovirus 3bovine parainfluenza virus 3 (BPIV-3)Human respirovirus 1human parainfluenza virus 1 (HPIV-1)Human respirovirus 3human parainfluenza virus 3 (HPIV-3)Murine respirovirus*Sendai virus (SeV)Porcine respirovirus 1porcine parainfluenza virus 1 (PPIV-1)RubulavirusAchimota rubulavirus 1Achimota virus 1 (AchPV-1)Achimota rubulavirus 2Achimota virus 2 (AchPV-2)Bat mumps rubulavirusbat mumps virus (BMV)Canine rubulavirusparainfluenza virus 5 (PIV-5)Hervey virusHervey virus (HerV)Human rubulavirus 2human parainfluenza virus 2 (HPIV-2)Human rubulavirus 4human parainfluenza virus 4a (HPIV-4a)human parainfluenza virus 4b (HPIV-4b)Mapuera rubulavirusMapuera virus (MapV)Menangle rubulavirusMenangle virus (MenPV)Mumps rubulavirus*mumps virus (MuV)Porcine rubulavirusLa Piedad Michoacán Mexico virus (LPMV)Simian rubulavirussimian virus 41 (SV-41)Sosuga rubulavirusSosuga virusTeviot rubulavirusTeviot virus (TevPV)Tioman rubulavirusTioman virus (TioPV)Tuhoko rubulavirus 1Tuhoko virus 1 (ThkPV-1)Tuhoko rubulavirus 2Tuhoko virus 2 (ThkPV-2)Tuhoko rubulavirus 3Tuhoko virus 3 (ThkPV-3) Table legend: "*" denotes type species. Beilong virus is now known to be a member of the family.[7] It was isolated from rat kidney and its pathogenic potential is unknown. J virus is very similar to Beilong virus and probably belongs in the same genus. Both have features that differ from the other genera in this family. Tailam virus may also belong in this genus. Two other viruses belong to this clade - Mount Mabu Lophuromys virus 1and Feline paramyxovirus. The genus Jeilongvirus has been proposed for these viruses.[8] The relations between the Salmon paramyxovirus and the others have been poorly studied to date and their relationship to the other members of this genus is not currently known. Another virus in this family is Anaconda paramyxovirus.[9] Bank vole virus, Mossman virus and Nariva virus are three paramyxoviruses that probably belong in a new genus.[10] Viral replication is cytoplasmic. Entry into the host cell is achieved by viral attachment to host cell. Replication follows the negative-stranded RNA virus replication model. Negative-stranded RNA virus transcription, using polymerase stuttering, is the method of transcription. Translation takes place by leaky scanning, ribosomal shunting, and RNA termination-reinitiation. The virus exits the host cell by budding. Human, vertebrates, and birds serve as the natural hosts. Transmission route is airborne particles.[4] The Paramyxoviridae are able to undergo mRNA editing, which produces different proteins from the same mRNA transcript by slipping back one base to read off in a different ORF due to the presence of secondary structures such as pseudoknots. Paramyxoviridae also undergo translational stuttering to produce the poly (A) tail at the end of mRNA transcripts by repeatedly moving back one nucleotide at a time at the end of the RNA template.[citation needed] GenusHost detailsTissue tropismEntry detailsRelease detailsReplication siteAssembly siteTransmissionAvulavirusBirdsNoneGlycoproteinBuddingCytoplasmCytoplasmContact: feces; contact: secretions (from nose, mouth, eyes)MorbillivirusHumans; dogs; cats; cetaceansNoneGlycoproteinBuddingCytoplasmCytoplasmAerosolsAquaparamyxovirusFishNoneGlycoproteinBuddingCytoplasmCytoplasmUnknownHenipavirusBatsNoneGlycoproteinBuddingCytoplasmCytoplasmZoonosis; animal biteRespirovirusRodents; humansNoneGlycoproteinBuddingCytoplasmCytoplasmAerosolsRubulavirusHumans; apes; pigs; dogsNoneGlycoproteinBuddingCytoplasmCytoplasmAerosols; salivaFerlavirusUnknownNoneGlycoproteinBuddingCytoplasmCytoplasmUnknown Virions are enveloped and can be spherical or pleomorphic and capable of producing filamentous virions. The diameter is around 150 nm. Genomes are linear, around 15kb in length.[2][4] Fusion proteins and attachment proteins appear as spikes on the virion surface. Matrix proteins inside the envelope stabilise virus structure. The nucleocapsid core is composed of the genomic RNA, nucleocapsid proteins, phosphoproteins and polymerase proteins. GenusStructureSymmetryCapsidGenomic arrangementGenomic segmentationAvulavirusSphericalEnvelopedLinearMonopartiteMorbillivirusSphericalEnvelopedLinearMonopartiteAquaparamyxovirusSphericalEnvelopedLinearMonopartiteHenipavirusSphericalEnvelopedLinearMonopartiteRespirovirusSphericalEnvelopedLinearMonopartiteRubulavirusPleomorphicEnvelopedLinearMonopartiteFerlavirusSphericalEnvelopedLinearMonopartite Paramyxovirus genome structure The genome is nonsegmented, negative-sense RNA, 15-19 kilobases in length, and contains six to 10 genes. Extracistronic (noncoding) regions include: A 3' leader sequence, 50 nucleotides in length, which acts as a transcriptional promoter. A 5' trailer sequence, 50-161 nucleotides long Intergenomic regions between each gene, which are three nucleotides long for morbilliviruses, respiroviruses, and henipaviruses, and variable length (one-56 nucleotides) for rubulaviruses. Each gene contains transcription start/stop signals at the beginning and end, which are transcribed as part of the gene. Gene sequence within the genome is conserved across the family due to a phenomenon known as transcriptional polarity (see Mononegavirales) in which genes closest to the 3' end of the genome are transcribed in greater abundance than those towards the 5' end. This is a result of structure of the genome. After each gene is transcribed, the RNA-dependent RNA polymerase pauses to release the new mRNA when it encounters an intergenic sequence. When the RNA polymerase is paused, a chance exists that it will dissociate from the RNA genome. If it dissociates, it must re-enter the genome at the leader sequence, rather than continuing to transcribe the length of the genome. The result is that the further downstream genes are from the leader sequence, the less they will be transcribed by RNA polymerase. Evidence for a single promoter model was verified when viruses were exposed to UV light. UV radiation can cause dimerization of RNA, which prevents transcription by RNA polymerase. If the viral genome follows a multiple promoter model, the level inhibition of transcription should correlate with the length of the RNA gene. However, the genome was best described by a single promoter model. When paramyxovirus genome was exposed to UV light, the level of inhibition of transcription was proportional to the distance from the leader sequence. That is, the further the gene is from the leader sequence, the greater the chance of RNA dimerization inhibiting RNA polymerase. The virus takes advantage of the single promoter model by having its genes arranged in relative order of protein needed for successful infection. For example, nucleocapsid protein, N, is needed in greater amounts than RNA polymerase, L. Viruses in the Paramyxoviridae family are also antigenically stable, meaning that the glycoproteins on the viruses are consistent between different strains of the same type. Two reasons for this phenomenon are posited: The first is that the genome is nonsegmented, thus cannot undergo genetic reassortment. For this process to occur, segments needed as reassortment happen when segments from different strains are mixed together to create a new strain. With no segments, nothing can be mixed with one another, so no antigenic shift occurs. The second reason relates to the idea of antigenic drift. Since RNA-dependent RNA polymerase does not have an error-checking function, many mutations are made when the RNA is processed. These mutations build up and eventually new strains are created. Due to this concept, one would expect that paramyxoviruses should not be antigenically stable; however, the opposite is seen to be true. The main hypothesis behind why the viruses are antigenically stable is that each protein and amino acid has an important function. Thus, any mutation would lead to a decrease or total loss of function, which would in turn cause the new virus to be less efficient. These viruses would not be able to survive as long compared to the more virulent strains, and so would die out. Many paramyxovirus genomes follow the "rule of six". The total length of the genome is almost always a multiple of six. This is probably due to the advantage of having all RNA bound by N protein (since N binds hexamers of RNA). If RNA is left exposed, the virus does not replicate efficiently. The gene sequence is: Nucleocapsid - phosphoprotein - matrix - fusion - attachment - large (polymerase) N - the nucleocapsid protein associates with genomic RNA (one molecule per hexamer) and protects the RNA from nuclease digestion P - the phosphoprotein binds to the N and L proteins and forms part of the RNA polymerase complex M - the matrix protein assembles between the envelope and the nucleocapsid core, it organizes and maintains virion structure F - the fusion protein projects from the envelope surface as a trimer, and mediates cell entry by inducing fusion between the viral envelope and the cell membrane by class I fusion. One of the defining characteristics of members of the family Paramyxoviridae is the requirement for a neutral pH for fusogenic activity. H/HN/G - the cell attachment proteins span the viral envelope and project from the surface as spikes. They bind to proteins on the surface of target cells to facilitate cell entry. Proteins are designated H (hemagglutinin) for morbilliviruses as they possess haemagglutination activity, observed as an ability to cause red blood cells to clump in laboratory tests. HN (Hemagglutinin-neuraminidase) attachment proteins occur in respiroviruses, rubulaviruses and avulaviruses. These possess both haemagglutination and neuraminidase activity, which cleaves sialic acid on the cell surface, preventing viral particles from reattaching to previously infected cells. Attachment proteins with neither haemagglutination nor neuraminidase activity are designated G (glycoprotein). These occur in henipaviruses. L - the large protein is the catalytic subunit of RNA-dependent RNA polymerase (RDRP) Accessory proteins - a mechanism known as RNA editing (see Mononegavirales) allows multiple proteins to be produced from the P gene. These are not essential for replication but may aid in survival in vitro or may be involved in regulating the switch from mRNA synthesis to antigenome synthesis. Phylogenetic tree based on the N protein sequences of selected paramyxovirusesVirus names are as follows: avian paramyxovirus 6 (APMV-6); Atlantic salmon paramyxovirus; Beilong virus (BeiPV) ; bovine parainfluenza virus 3 (bPIV3); canine distemper virus (CDV); Cedar virus (CedV); Fer-de-lance virus (FdlPV) ; Hendra virus (HeV); human parainfluenza virus 2 (hPIV2); human parainfluenza virus 3 (hPIV3) ; human parainfluenza virus 4a (hPIV4a) ; human parainfluenza virus 4b (hPIV4b); J virus (JPV); Menangle virus (MenPV); measles virus (MeV); Mossman virus (MosPV); Mapuera virus (MprPV); mumps virus (MuV); Newcastle disease virus (NDV); Nipah virus, Bangladesh strain (NiV-B); Nipah virus, Malaysian strain (NiV-M); parainfluenza virus 5 (PIV5); peste-des-petits-ruminants (PPRV); porcine rubulavirus (PorPV); rinderpest virus (RPV); Salem virus (SalPV); Sendai virus (SeV); simian virus 41 (SV41); Tioman virus (TioPV); tupaia paramyxovirus (TupPV).[11] A number of important human diseases are caused by paramyxoviruses. These include mumps, measles, which caused around 733,000 deaths in 2000,[12] and respiratory syncytial virus (RSV), which is the major cause of bronchiolitis and pneumonia in infants and children. The human parainfluenza viruses (HPIV) are the second most common causes of respiratory tract disease in infants and children. There are four types of HPIVs, known as HPIV-1, HPIV-2, HPIV-3 and HPIV-4. HPIV-1 and HPIV-2 may cause cold-like symptoms, along with croup in children. HPIV-3 is associated with bronchiolitis, bronchitis, and pneumonia. HPIV-4 is less common than the other types, and is known to cause mild to severe respiratory tract illnesses.[13] Paramyxoviruses are also responsible for a range of diseases in other animal species, for example canine distemper virus (dogs), phocine distemper virus (seals), cetacean morbillivirus (dolphins and porpoises), Newcastle disease virus (birds), and rinderpest virus (cattle). Some paramyxoviruses such as the henipaviruses are zoonotic pathogens, occurring naturally in an animal host, but also able to infect humans. Hendra virus (HeV) and Nipah virus (NiV) in the genus Henipavirus have emerged in humans and livestock in Australia and Southeast Asia. Both viruses are contagious, highly virulent, and capable of infecting a number of mammalian species and causing potentially fatal disease. Due to the lack of a licensed vaccine or antiviral therapies, HeV and NiV are designated as Biosafety level (BSL) 4 agents. The genomic structure of both viruses is that of a typical paramyxovirus.[14] In the past few decades, paramyxoviruses have been discovered from terrestrial, volant and aquatic animals, demonstrating a vast host range and great viral genetic diversity. As molecular technology advances and viral surveillance programs are implemented, the discovery of new viruses in this group is increasing.[5] The evolution of paramyxoviruses is still debated. Using pneumoviruses (mononegaviral family Pneumoviridae) as an outgroup, paramyxoviruses can be divided into two clades: one consisting of avulaviruses and rubulaviruses and one consisting of respiroviruses, henipaviruses, and morbilliviruses.[15]Within the second clade the respiroviruses appear to be the basal group. The respirovirus-henipavirus-morbillivirus clade may be basal to the avulavirus-rubulavirus clade.

Poliovirus

Poliovirus, the causative agent of polio (also known as poliomyelitis), is a serotype of the species Enterovirus C, in the family of Picornaviridae.[1] Poliovirus is composed of an RNA genome and a protein capsid. The genome is a single-stranded positive-sense RNA genome that is about 7500 nucleotides long.[2] The viral particle is about 30 nm in diameter with icosahedral symmetry. Because of its short genome and its simple composition—only RNA and a nonenveloped icosahedral protein coat that encapsulates it, poliovirus is widely regarded as the simplest significant virus.[3] Poliovirus was first isolated in 1909 by Karl Landsteiner and Erwin Popper.[4] The structure of the virus was first elucidated using x-ray diffraction by a team at Birkbeck College led by Rosalind Franklin,[5][6] showing that the polio virus to have icosahedral symmetry.[7] In 1981, the poliovirus genome was published by two different teams of researchers: by Vincent Racaniello and David Baltimore at MIT[8] and by Naomi Kitamura and Eckard Wimmer at Stony Brook University.[9] Poliovirus is one of the most well-characterized viruses, and has become a useful model system for understanding the biology of RNA viruses. Contents 1Replication cycle 2Origin and serotypes 3Pathogenesis 4Immune system avoidance 5PVR transgenic mouse 6Cloning and synthesis 7Modification for therapies 8References 9External links The replication cycle of poliovirus is initiated (1) by binding to the cell surface receptor CD155. The virion is taken up via endocytosis, and the viral RNA is released (2). Translation of the viral RNA occurs by an IRES-mediated mechanism (3). The polyprotein is cleaved, yielding mature viral proteins (4). The positive-sense RNA serves as template for complementary negative-strand synthesis, producing double-stranded replicative form (RF) RNA(5). Many positive strand RNA copies are produced from the single negative strand (6). The newly synthesized positive-sense RNA molecules can serve as templates for translation of more viral proteins (7) or can be enclosed in a capsid (8), which ultimately generates progeny virions. Lysis of the infected cell results in release of infectious progeny virions (9).[10] Poliovirus infects human cells by binding to an immunoglobulin-like receptor, CD155 (also known as the poliovirus receptor or PVR)[11][12] on the cell surface.[13] Interaction of poliovirus and CD155 facilitates an irreversible conformational change of the viral particle necessary for viral entry.[14][15] Attached to the host cell membrane, entry of the viral nucleic acid was thought to occur one of two ways: via the formation of a pore in the plasma membrane through which the RNA is then "injected" into the host cell cytoplasm, or that the virus is taken up by receptor-mediated endocytosis.[16] Recent experimental evidence supports the latter hypothesis and suggests that poliovirus binds to CD155 and is taken up by endocytosis. Immediately after internalization of the particle, the viral RNA is released.[17] Poliovirus is a positive-stranded RNA virus. Thus, the genome enclosed within the viral particle can be used as messenger RNA and immediately translatedby the host cell. On entry, the virus hijacks the cell's translation machinery, causing inhibition of cellular protein synthesis in favor of virus-specific protein production.[18] Unlike the host cell's mRNAs, the 5' end of poliovirus RNA is extremely long—over 700 nucleotides—and highly structured. This region of the viral genome is called internal ribosome entry site (IRES), and it directs translation of the viral RNA. Genetic mutations in this region prevent viral protein production.[19][20][21] The first IRES to be discovered was found in poliovirus RNA.[22] Poliovirus mRNA is translated as one long polypeptide. This polypeptide is then autocleaved by internal proteases into about 10 individual viral proteins. Not all cleavages occur with the same efficiency. Therefore, the amounts of proteins produced by the polypeptide cleavage vary: for example, smaller amounts of 3Dpol are produced than those of capsid proteins, VP1-4.[23][24] These individual viral proteins are:[3][25] The genomic structure of poliovirus type 1[10] 3Dpol, an RNA dependent RNA polymerase whose function is to make multiple copies of the viral RNA genome 2Apro and 3Cpro/3CDpro, proteases which cleave the viral polypeptide VPg (3B), a small protein that binds viral RNA and is necessary for synthesis of viral positive and negative strand RNA 2BC, 2B, 2C (an ATPase)[26], 3AB, 3A, 3B proteins which comprise the protein complex needed for virus replication. VP0, which is further cleaved into VP2 and VP4, VP1 and VP3, proteins of the viral capsid After translation, transcription and genome replication which involve a single process (synthesis of (+) RNA) is realized. For the infecting (+) RNA to be replicated, multiple copies of (−) RNA must be transcribed and then used as templates for (+) RNA synthesis. Replicative intermediates (RIs) which are an association of RNA molecules consisting of a template RNA and several growing RNAs of varying length, are seen in both the replication complexes for (−) RNAs and (+) RNAs. The primer for both (+) and (−) strand synthesis is the small protein VPg, which is uridylylated at the hydroxyl group of a tyrosine residue by the poliovirus RNA polymerase at a cis-acting replication element located in a stem-loop in the virus genome. Some of the (+) RNA molecules are used as templates for further (−) RNA synthesis, some function as mRNA, and some are destined to be the genomes of progeny virions.[23] In the assembly of new virus particles (i.e. the packaging of progeny genome into a procapsid which can survive outside the host cell), including, respectively:[27] Five copies each of VP0, VP3, and VP1 which its N termini and VP4 form interior surface of capsid, assemble into a 'pentamer' and 12 pentamers form a procapsid. (The outer surface of capsid is consisting of VP1, VP2, VP3; C termini of VP1 and VP3 form the canyons which around each of the vertices; around this time, the 60 copies of VP0 are cleaved into VP4 and VP2.) Each procapsid acquires a copy of the virus genome, with VPg still attached at the 5' end. Fully assembled poliovirus leaves the confines of its host cell by lysis[28] 4 to 6 hours following initiation of infection in cultured mammalian cells.[29] The mechanism of viral release from the cell is unclear,[2] but each dying cell can release up to 10,000 polio virions.[29] Drake demonstrated that poliovirus is able to undergo multiplicity reactivation.[30] That is, when polioviruses were irradiated with UV light and allowed to undergo multiple infections of host cells, viable progeny could be formed even at UV doses that inactivated the virus in single infections. Poliovirus is structurally similar to other human enteroviruses (coxsackieviruses, echoviruses, and rhinoviruses), which also use immunoglobulin-like molecules to recognize and enter host cells.[12] Phylogenetic analysis of the RNA and protein sequences of poliovirus suggests that it may have evolved from a C-cluster Coxsackie A virus ancestor, that arose through a mutation within the capsid.[31] The distinct speciation of poliovirus probably occurred as a result of change in cellular receptor specificity from intercellular adhesion molecule-1 (ICAM-1), used by C-cluster Coxsackie A viruses, to CD155; leading to a change in pathogenicity, and allowing the virus to infect nervous tissue. The mutation rate in the virus is relatively high even for an RNA virus with a synonymous substitution rate of 1.0 x 10−2 substitutions/site/year and non synonymous substitution rate of 3.0 x 10−4 substitutions/site/year.[32] Base distribution within the genome is not random with adenosine being less common than expected at the 5' end and higher at the 3' end.[33] Codon use is not random with codons ending in adenosine being favoured and those ending in cytosine or guanine being avoided. Codon use differs between the three genotypes and appears to be driven by mutation rather than selection.[34] The three serotypes of poliovirus, PV-1, PV-2, and PV-3, each have a slightly different capsid protein. Capsid proteins define cellular receptor specificity and virus antigenicity. PV-1 is the most common form encountered in nature, but all three forms are extremely infectious.[4] As of November 2015, wild PV-1 is highly localized to regions in Pakistan and Afghanistan. Wild PV-2 was declared eradicated in September 2015 after last being detected in October 1999 in Uttar Pradesh, India.[35] As of November 2015, wild PV-3 has not been seen since its 2012 detection in parts of Nigeria and Pakistan.[36] Specific strains of each serotype are used to prepare vaccines against polio. Inactive polio vaccine is prepared by formalin inactivation of three wild, virulent reference strains, Mahoney or Brunenders (PV-1), MEF-1/Lansing (PV-2), and Saukett/Leon (PV-3). Oral polio vaccine contains live attenuated (weakened) strains of the three serotypes of poliovirus. Passaging the virus strains in monkey kidney epithelial cells introduces mutations in the viral IRES, and hinders (or attenuates) the ability of the virus to infect nervous tissue.[29] Polioviruses were formerly classified as a distinct species belonging to the genus Enterovirus in the family Picornaviridae. In 2008, the Poliovirus species was eliminated and the three serotypes were assigned to the species Human enterovirus C (later renamed Enterovirus C), in the genus Enterovirus in the family Picornaviridae. The type species of the genus Enterovirus was changed from Poliovirus to (Human) Enterovirus C.[37] Main article: Polio Electron micrograph of poliovirus The primary determinant of infection for any virus is its ability to enter a cell and produce additional infectious particles. The presence of CD155 is thought to define the animals and tissues that can be infected by poliovirus. CD155 is found (outside of laboratories) only on the cells of humans, higher primates, and Old World monkeys. Poliovirus is, however, strictly a human pathogen, and does not naturally infect any other species (although chimpanzees and Old World monkeys can be experimentally infected).[38] The CD155 gene appears to have been subject to positive selection.[39] The protein has several domains of which domain D1 contains the polio virus binding site. Within this domain, 37 amino acids are responsible for binding the virus. Poliovirus is an enterovirus. Infection occurs via the fecal-oral route, meaning that one ingests the virus and viral replication occurs in the alimentary tract.[40] Virus is shed in the feces of infected individuals. In 95% of cases only a primary, transient presence of viremia (virus in the bloodstream) occurs, and the poliovirus infection is asymptomatic. In about 5% of cases, the virus spreads and replicates in other sites such as brown fat, reticuloendothelialtissue, and muscle. The sustained viral replication causes secondary viremia and leads to the development of minor symptoms such as fever, headache, and sore throat.[41] Paralytic poliomyelitis occurs in less than 1% of poliovirus infections. Paralytic disease occurs when the virus enters the central nervous system (CNS) and replicates in motor neurons within the spinal cord, brain stem, or motor cortex, resulting in the selective destruction of motor neurons leading to temporary or permanent paralysis. In rare cases, paralytic poliomyelitis leads to respiratory arrest and death. In cases of paralytic disease, muscle pain and spasms are frequently observed prior to onset of weakness and paralysis. Paralysis typically persists from days to weeks prior to recovery.[42] In many respects, the neurological phase of infection is thought to be an accidental diversion of the normal gastrointestinal infection.[16] The mechanisms by which poliovirus enters the CNS are poorly understood. Three nonmutually exclusive hypotheses have been suggested to explain its entry. All theories require primary viremia. The first hypothesis predicts that virions pass directly from the blood into the central nervous system by crossing the blood-brain barrier independent of CD155.[43] A second hypothesis suggests that the virions are transported from peripheral tissues that have been bathed in the viremic blood, for example muscle tissue, to the spinal cord through nerve pathways via retrograde axonal transport.[44][45][46] A third hypothesis is that the virus is imported into the CNS via infected monocytes or macrophages.[10] Poliomyelitis is a disease of the central nervous system. However, CD155 is believed to be present on the surface of most or all human cells. Therefore, receptor expression does not explain why poliovirus preferentially infects certain tissues. This suggests that tissue tropism is determined after cellular infection. Recent work has suggested that the type I interferon response (specifically that of interferon alpha and beta) is an important factor that defines which types of cells support poliovirus replication.[47] In mice expressing CD155 (through genetic engineering) but lacking the type I interferon receptor, poliovirus not only replicates in an expanded repertoire of tissue types, but these mice are also able to be infected orally with the virus.[48] CD155 molecules complexed with a poliovirus particle. Reconstructed image from cryo-electron microscopy. Poliovirus uses two key mechanisms to evade the immune system. First, it is capable of surviving the highly acidic conditions of the stomach, allowing the virus to infect the host and spread throughout the body via the lymphatic system.[3] Second, because it can replicate very quickly, the virus overwhelms the host organs before an immune response can be mounted.[49] If detail is given at the attachment phase; poliovirus with canyons on the virion surface have virus attachment sites located in pockets at the canyon bases. The canyons are too narrow for access by antibodies, so the virus attachment sites are protected from the host's immune surveillance, while the remainder of the virion surface can mutate to avoid the host's immune response.[50] Individuals who are exposed to poliovirus, either through infection or by immunization with polio vaccine, develop immunity. In immune individuals, antibodies against poliovirus are present in the tonsils and gastrointestinal tract (specifically IgA antibodies) and are able to block poliovirus replication; IgG and IgM antibodies against poliovirus can prevent the spread of the virus to motor neurons of the central nervous system.[29] Infection with one serotype of poliovirus does not provide immunity against the other serotypes, however second attacks within the same individual are extremely rare.[citation needed]

Kuru

Prion disease suffered by the Fore due to consuming humans through cannibalism specifically by consuming the brains/nervous system of the dead. Symptoms include insomnia, lack of coordination/balance, eventually death.

Mycobacterium tuberculosis

RIPE (rifampin, isoniazid, pyrazinamide, ethambutol)

Rickettsia rickettsii

Rocky Mountain Spotted Fever

Rotavirus

Rotavirus is a genus of double-stranded RNA viruses in the family Reoviridae. Rotaviruses are the most common cause of diarrhoeal disease among infants and young children.[1] Nearly every child in the world is infected with a rotavirus at least once by the age of five.[2] Immunity develops with each infection, so subsequent infections are less severe; adults are rarely affected.[3] There are ten species of the genus, referred to as A, B, C, D, E, F, G, H, I and J. Rotavirus A, the most common species, causes more than 90% of rotavirus infections in humans. The virus is transmitted by the faecal-oral route. It infects and damages the cells that line the small intestine and causes gastroenteritis (which is often called "stomach flu" despite having no relation to influenza). Although Rotavirus was discovered in 1973 by Ruth Bishop and her colleagues by electron micrograph images[4] and accounts for approximately one third of hospitalisations for severe diarrhoea in infants and children,[5] its importance has historically been underestimated within the public health community, particularly in developing countries.[6] In addition to its impact on human health, rotavirus also infects animals, and is a pathogen of livestock.[7] Rotaviral enteritis is usually an easily managed disease of childhood, but in 2013, rotaviruses caused 37 percent of deaths of children from diarrhoea and 215,000 deaths worldwide,[8] and almost two million more became severely ill.[6] Most of these deaths occurred in developing countries.[9] In the United States, before initiation of the rotavirus vaccination programme in the 2000s, rotavirus caused about 2.7 million cases of severe gastroenteritis in children, almost 60,000 hospitalisations, and around 37 deaths each year.[10] Following rotavirus vaccine introduction in the United States, hospitalisation rates have fallen significantly.[11][12] Public health campaigns to combat rotavirus focus on providing oral rehydration therapy for infected children and vaccination to prevent the disease.[13] The incidence and severity of rotavirus infections has declined significantly in countries that have added rotavirus vaccine to their routine childhood immunisation policies.[14][15][16] Contents 1Virology1.1Types of rotavirus1.2Structure1.3Proteins1.4Replication 2Transmission 3Signs and symptoms 4Disease mechanisms 5Immune responses5.1Specific responses5.2Innate responses5.3Markers of protection 6Diagnosis and detection 7Treatment and prognosis 8Prevention 9Epidemiology 10Other animals 11History 12References 13External links There are nine species of rotavirus, referred to as A, B, C, D, E, F, G, H, I and J.[17][18] Humans are primarily infected by the species rotavirus A. A-E species cause disease in other animals,[19]species E and H in pigs, D, F and G in birds, I in cats and J in bats.[20][21][22][23] Within rotavirus A there are different strains, called serotypes.[24] As with influenza virus, a dual classification system is used based on two proteins on the surface of the virus. The glycoprotein VP7 defines the G serotypes and the protease-sensitive protein VP4 defines P serotypes.[25] Because the two genes that determine G-types and P-types can be passed on separately to progeny viruses, different combinations are found.[25] A whole genome genotyping system has been established for rotavirus A, which has been used to determine the origin of atypical strains.[26] The prevalence of the individual G-types and P-types varies between, and within, countries and years.[27] There are at least 32 G types and 47 P types but in infections of humans only a few combinations of G and P types predominate. They are G1P[8], G2P[4], G3P[8], G4P[8], G9P[8] and G12P[8].[18] The genome of rotaviruses consists of 11 unique double helix molecules of RNA (dsRNA) which are 18,555 nucleotides in total. Each helix, or segment, is a gene, numbered 1 to 11 by decreasing size. Each gene codes for one protein, except genes 9, which codes for two.[28] The RNA is surrounded by a three-layered icosahedral protein capsid. Viral particles are up to 76.5 nm in diameter[29][30] and are not enveloped. A simplified diagram of the location of rotavirus structural proteins There are six viral proteins (VPs) that form the virus particle (virion). These structural proteins are called VP1, VP2, VP3, VP4, VP6 and VP7. In addition to the VPs, there are six nonstructural proteins (NSPs), that are only produced in cells infected by rotavirus. These are called NSP1, NSP2, NSP3, NSP4, NSP5 and NSP6.[19] At least six of the twelve proteins encoded by the rotavirus genome bind RNA.[31] The role of these proteins play in rotavirus replication is not entirely understood; their functions are thought to be related to RNA synthesis and packaging in the virion, mRNA transport to the site of genome replication, and mRNA translation and regulation of gene expression.[32]

Rubivirus

Rubella virus (RuV) is the pathogenic agent of the disease rubella, and is the main cause of congenital rubella syndrome when infection occurs during the first weeks of pregnancy. Rubella virus is the only member of the genus Rubivirus and belongs to the family of Matonaviridae, whose members commonly have a genome of single-stranded RNA of positive polarity which is enclosed by an icosahedral capsid. The molecular basis for the causation of congenital rubella syndrome are not yet completely clear, but in vitro studies with cell lines showed that rubella virus has an apoptotic effect on certain cell types. There is evidence for a p53-dependent mechanism.[1] Contents 1Taxonomy 2Creation of New Matonaviridae Family2.1Transmission2.2Morphology2.3Phylogeny 3Structure 4Genome 5Replication 6Capsid protein 7Epidemiology 8Literature 9References 10External links Group: ssRNA(+) Order: Unassigned Family: Matonaviridae Genus: Rubivirus Rubella virus [2] Until 2018, Rubiviruses were classified as part of the family Togaviridae, but have since been changed to be the sole genus of the family Matonaviridae. This new family is named after George de Maton, who in 1814 first distinguished rubella from measles and scarlet fever.[3] This change was made by the International Committee on the Taxonomy of Viruses (ICTV), the central governing body for viral classification. Matonaviridae remains part of the realm that it was already in as Togaviridae, Riboviria, because of its RNA genome and RNA dependent RNA polymerase.[3] There were several reasons given for the change. The other members of the Togaviridae were the genus Alphavirus. These are usually arthropod-borne (ARBO) viruses. RuV, on the other hand, is a respiratory-transmitted between humans.[3] While alphavirus virions are spherical and contain an icosahedral nucleocapsid, RuV virions are pleiomorphic and do not contain icosahedral nucleocapsids.[3] ICTV analyzed the sequence of RuV and compared its phylogeny to that of togaviruses. They concluded: The spherical virus particles (virions) of Matonaviridae have a diameter of 50 to 70 nm and are covered by a lipid membrane (viral envelope), derived from the host cell membrane. There are prominent "spikes" (projections) of 6 nm composed of the viral envelope proteins E1 and E2 embedded in the membrane.[4] Inside the lipid envelope is a capsid of 40 nm in diameter. The E1 glycoprotein is considered immunodominant in the humoral response induced against the structural proteins and contains both neutralizing and hemagglutinating determinants. GenusStructureSymmetryCapsidGenomic arrangementGenomic segmentationRubivirusIcosahedralT=4EnvelopedLinearMonopartite [5] The genome has 9,762 nucleotides and encodes 2 nonstructural polypeptides (p150 and p90) within its 5′-terminal two-thirds and 3 structural polypeptides (C, E2, and E1) within its 3′-terminal one-third.[6] Both envelope proteins E1 and E2 are glycosylated. There are three sites that are highly conserved in Matonaviruses: a stem-and-loop structure at the 5' end of the genome, a 51-nucleotide conserved sequence near the 5' end of the genome and a 20-nucleotide conserved sequence at the subgenomic RNA start site. Homologous sequences are present in the rubella genome.[6] The genome encodes several non-coding RNA structures; among them is the rubella virus 3' cis-acting element, which contains multiple stem-loops, one of which has been found to be essential for viral replication.[7] The only significant region of homology between rubella and the alphaviruses is located at the NH2 terminus of non structural protein 3. This sequence has helicase and replicase activity. In the rubella genome these occur in the opposite orientation to that found in the alphaviruses indicating that a genome rearrangement has occurred. The genome has the highest G+C content of any currently known single stranded RNA virus (~70%).[8] Despite this high GC content its codon use is similar to that of its human host. The virus attach to the cell surface via specific receptors and are taken up by an endosome being formed. At the neutral pH outside of the cell the E2 envelope protein covers the E1 protein. The dropping pH inside the endosome frees the outer domain of E1 and causes the fusion of the viral envelope with the endosomal membrane. Thus, the capsid reaches the cytosol, decays and releases the genome The (+)ssRNA (positive, single-stranded RNA) at first only acts as a template for the translation of the non-structural proteins, which are synthesized as a large polyprotein and are then cut into single proteins. The sequences for the structural proteins are first replicated by the viral RNA polymerase (Replicase) via a complementary (-)ssRNA as a template and translated as a separate short mRNA. This short subgenomic RNA is additionally packed in a virion.[9] Translation of the structural proteins produces a large polypeptide (110 Dalton). This is then endoproteolytically cut into E1, E2 and the capsid protein. E1 and E2 are type I transmembrane proteinswhich are transported into the endoplasmatic reticulum (ER) with the help of an N-terminal signal sequence. From the ER the heterodimeric E1·E2-complex reaches the Golgi apparatus, where the budding of new virions occurs (unlike alpha viruses, where budding occurs at the plasma membrane. The capsid proteins on the other hand stay in the cytoplasm and interact with the genomic RNA, together forming the capsid.[10] GenusHost detailsTissue tropismEntry detailsRelease detailsReplication siteAssembly siteTransmissionRubivirusHumansNoneClathrin-mediated endocytosisSecretionCytoplasmCytoplasmAerosol [5] The capsid protein (CP) has different functions.[11] Its main tasks are the formation of homooligomeres to form the capsid, and the binding of the genomic RNA. Further is it responsible for the aggregation of RNA in the capsid, it interacts with the membrane proteins E1 and E2 and binds the human host-protein p32 which is important for replication of the virus in the host.[12] As opposed to alpha viruses the capsid does not undergo autoproteolysis, rather is it cut off from the rest of the polyprotein by the signal-peptidase. Production of the capsid happens at the surface of intracellular membranes simultaneously with the budding of the virus.[13] On the basis of differences in the sequence of the E1 protein, two genotypes have been described which differ by 8 - 10%. These have been subdivided into 13 recognised genotypes - 1a, 1B, 1C, 1D, 1E, 1F, 1G, 1h, 1i, 1j, 2A, 2B and 2C. For typing, the WHO recommends a minimum window that includes nucleotides 8731 to 9469.[14] Genotypes 1a, 1E, 1F, 2A and 2B have been isolated in China. Genotype 1j has only been isolated from Japan and the Philippines. Genotype 1E is found in Africa, the Americas, Asia and Europe. Genotype 1G has been isolated in Belarus, Cote d'Ivoire and Uganda. Genotype 1C is endemic only in Central and South America. Genotype 2B has been isolated in South Africa. Genotype 2C has been isolated in Russia.

Variola virus

SMALL POX Smallpox was an infectious disease caused by one of two virus variants, Variola major and Variola minor.[7] The last naturally occurring case was diagnosed in October 1977, and the World Health Organization (WHO) certified the global eradication of the disease in 1980.[10] The risk of death following contracting the disease was about 30%, with higher rates among babies.[6][11] Often those who survived had extensive scarring of their skin, and some were left blind.[6] The initial symptoms of the disease included fever and vomiting.[5] This was followed by formation of sores in the mouth and a skin rash.[5] Over a number of days the skin rash turned into characteristic fluid-filled bumps with a dent in the center.[5] The bumps then scabbed over and fell off, leaving scars.[5] The disease was spread between people or via contaminated objects.[6][12] Prevention was by the smallpox vaccine.[9] Once the disease had developed, certain antiviral medication may have helped.[9] The origin of smallpox is unknown.[13] The earliest evidence of the disease dates to the 3rd century BCE in Egyptian mummies.[13] The disease historically occurred in outbreaks.[10] In 18th-century Europe, it is estimated 400,000 people per year died from the disease, and one-third of the cases resulted in blindness.[10][14] These deaths included four reigning monarchs and a queen consort.[10][14] Smallpox is estimated to have killed up to 300 million people in the 20th century[15][16] and around 500 million people in the last 100 years of its existence.[17] As recently as 1967, 15 million cases occurred a year.[10] Edward Jenner discovered in 1798 that vaccination could prevent smallpox.[10] In 1967, the WHO intensified efforts to eliminate the disease.[10]Smallpox is one of two infectious diseases to have been eradicated, the other being rinderpest in 2011.[18][19] The term "smallpox" was first used in Britain in the early 16th century to distinguish the disease from syphilis, which was then known as the "great pox".[20][21] Other historical names for the disease include pox, speckled monster, and red plague.[3][4][21] The incubation period between contraction and the first obvious symptoms of the disease was around 12 days. Once inhaled, variola major virus invaded the oropharyngeal (mouth and throat) or the respiratory mucosa, migrated to regional lymph nodes, and began to multiply. In the initial growth phase, the virus seemed to move from cell to cell, but by around the 12th day, lysis of many infected cells occurred and the virus was found in the bloodstream in large numbers, a condition known as viremia, which resulted in a second wave of multiplication in the spleen, bone marrow, and lymph nodes. The initial symptoms were similar to other viral diseases that are still extant, such as influenza and the common cold: fever of at least 38.3 °C (101 °F), muscle pain, malaise, headache and prostration. As the digestive tract was commonly involved, nausea and vomiting and backache often occurred. The prodrome, or preeruptive stage, usually lasted 2-4 days. By days 12-15, the first visible lesions - small reddish spots called enanthem - appeared on mucous membranes of the mouth, tongue, palate, and throat, and temperature fell to near-normal. These lesions rapidly enlarged and ruptured, releasing large amounts of virus into the saliva.[24] Smallpox virus preferentially attacked skin cells, causing the characteristic pimples, or macules, associated with the disease. A rash developed on the skin 24 to 48 hours after lesions on the mucous membranes appeared. Typically the macules first appeared on the forehead, then rapidly spread to the whole face, proximalportions of extremities, the trunk, and lastly to distal portions of extremities. The process took no more than 24 to 36 hours, after which no new lesions appeared.[24]At this point, variola major infection could take several very different courses, which resulted in four types of smallpox disease based on the Rao classification:[25]ordinary, modified, malignant (or flat), and hemorrhagic. Historically, ordinary smallpox had an overall fatality rate of about 30 percent, and the malignant and hemorrhagic forms were usually fatal.[26] Smallpox was caused by infection with Variola virus, which belongs to the genus Orthopoxvirus, the family Poxviridae and subfamily Chordopoxvirinae. Variola is a large brick-shaped virus measuring approximately 302 to 350 nanometers by 244 to 270 nm,[41] with a single linear double stranded DNAgenome 186 kilobase pairs (kbp) in size and containing a hairpin loop at each end.[42][43] The two classic varieties of smallpox are variola major and variola minor. Four orthopoxviruses cause infection in humans: variola, vaccinia, cowpox, and monkeypox. Variola virus infects only humans in nature, although primates and other animals have been infected in a laboratory setting. Vaccinia, cowpox, and monkeypox viruses can infect both humans and other animals in nature.[23] The life cycle of poxviruses is complicated by having multiple infectious forms, with differing mechanisms of cell entry. Poxviruses are unique among DNA viruses in that they replicate in the cytoplasm of the cell rather than in the nucleus. In order to replicate, poxviruses produce a variety of specialized proteins not produced by other DNA viruses, the most important of which is a viral-associated DNA-dependent RNA polymerase. Both enveloped and unenveloped virions are infectious. The viral envelope is made of modified Golgi membranes containing viral-specific polypeptides, including hemagglutinin.[42] Infection with either variola major or variola minor confers immunity against the other.[24]

HTLV-1 and HTLV-2

The human T-lymphotropic virus, human T-cell lymphotropic virus, or human T-cell leukemia-lymphoma virus (HTLV) family of viruses are a group of human retroviruses that are known to cause a type of cancer called adult T-cell leukemia/lymphoma and a demyelinating disease called HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLVs belong to a larger group of primate T-lymphotropic viruses (PTLVs). Members of this family that infect humans are called HTLVs, and the ones that infect Old World monkeys are called Simian T-lymphotropic viruses (STLVs). To date, four types of HTLVs (HTLV-1, HTLV-2, HTLV-3, and HTLV-4) and four types of STLVs (STLV-1, STLV-2, STLV-3, and STLV-5) have been identified. HTLV types HTLV-1 and HTLV-2 viruses are the first retroviruses which were discovered. Both belong to the oncovirus subfamily of retroviruses and can transform human lymphocytes so that they are self-sustaining in vitro.[1] The HTLVs are believed to originate from intraspecies transmission of STLVs. The HTLV-1 genome is diploid, composed of two copies of a single-stranded RNA virus whose genome is copied into a double-stranded DNA form that integrates into the host cell genome, at which point the virus is referred to as a provirus. A closely related virus is bovine leukemia virus BLV. The original name for HIV, the virus that causes AIDS, was HTLV-3. Confusingly, however, since reassignment, the AIDS virus is now called HIV and not HTLV-3. Contents 1HTLV-1 2HTLV-2 3HTLV-3 and HTLV-4 4Transmission 5Epidemiology 6Vaccination and treatments 7References 8External links Main article: Human T-lymphotropic virus 1 This article may be too technical for most readers to understand. Please help improve it to make it understandable to non-experts, without removing the technical details. (April 2017) (Learn how and when to remove this template message) HTLV-1 is an abbreviation for human T-cell lymphotropic virus type 1, also called human T-cell leukemia type 1, a virus that has been implicated in several kinds of diseases, including tropical spastic paraparesis, and as a virus cancer link for leukemia (see adult T-cell leukemia/lymphoma). HTLV-1 has six reported subtypes (subtypes A to F). The great majority of infections are caused by the cosmopolitan subtype A.[2] HTLV was discovered by Robert Galloand colleagues in 1980.[3] Between 1 in 20 and 1 in 25 infected people are thought to develop cancer as a result of the virus.[citation needed][4] HTLV-1 infection is thought to spread only through dividing cells since reverse transcriptase generates proviral DNA from genomic viral RNA, and the provirus is integrated into the host genome by viral integrase after transmission. Therefore, the quantification of provirus reflects the number of HTLV-1-infected cells. So, an increase in numbers of HTLV-1-infected cells using cell division, by actions of accessory viral genes, especially Tax, may provide an enhancement of infectivity. Tax expression induces proliferation, inhibits the apoptosis of HTLV-1-infected cells and, conversely, evokes the host immune response, including cytotoxic T cells, to kill virus-infected cells.[5] Interesting, HTLV-1 Tax viral gene is known to dampen innate antiviral signaling pathways to avoid host detection and elimination, through SOCS1 and Aryl Hydrocarbon Receptor Interacting Protein (AIP).[6][7] Figure 1. Mycosis fungoides,[8] a skin disease showing nodules and plaques composed of lymphocytes spread across the skin, has been associated with HTLV-II infection.[9] Figure 2. A phylogeny of the subtypes of HTLV and their relationships between endogenous and exogenous retroviruses in the human genome. HERV = human endogenous retrovirus, SFV = simian foamy virus.[10] Main article: Human T-lymphotropic virus 2 A virus closely related to HTLV-1, also discovered by Robert Gallo and colleagues. The family of Human T-lymphotropic virus (Figure 2) can be further categorized into four sub types. The figure also divides the retroviruses into exogenous and endogenous. Retroviruses can exist as two different forms: endogenous which consist of normal genetic components and exogenous which are horizontally transferred genetic components that are usually infectious agents that cause disease i.e. HIV. In (Figure 3) open reading frames (ORF) are shown which can if translated can predict which genes will be present and this can help to better understand human retroviruses. Of the four subtypes, HTLV-2 may be linked to Cutaneous T-cell lymphoma (CTCL).[9] In one study involving cultured lymphocytes from patients with mycosis fungoides (Figure 1), PCR amplification showed gene sequences of HTLV-II.[9] This finding may suggest a possible correlation with HTLV-2 and CTCL. Further research and studies must be conducted to show a positive relationship. HTLV-3 and HTLV-4 have been used to describe recently characterized viruses.[11][12][13] These viruses were discovered in 2005 in rural Cameroon, and were, it is presumed, transmitted from monkeys to hunters of monkeys through bites and scratches. HTLV-3 is similar to STLV-3 (Simian T-lymphotropic virus 3).[14] Multiple strains have been identified.[15] It expresses gag, pol, and env, among other proteins.[16] HTLV-4 is apparently substantially identical to STLV-4 hosted in gorillas. It is not yet known how much further transmission has occurred among humans, or whether the viruses can cause disease. The use of these names can cause some confusion, because the name HTLV-3 was one of the names for HIV in early AIDS literature, but has since fallen out of use.[17] The name HTLV-4 has also been used to describe HIV-2.[18] A large Canadian study documented this confusion among healthcare workers, where >90% of HTLV tests ordered by physicians were actually intended to be HIV tests.[19] Figure 3. ORF maps of HTLV type retroviruses.[8]Betaretroviruses (such as HERV-K) are found in mice, primates and sheep. Deltaretroviruses include bovine leukemia virus and HTLV-1 and -2. Gammaretroviruses include the murine leukemia virus and the feline leukemia virus but also viruses that infect reptiles and birds. Lentiviruses include HIV. Spumaviruses or foamyviruses include SFV and HERV-L. Abbreviations: LTR = long terminal repeat, consisting of the U3, R and U5 regions in the integrated provirus, gag = group-specific-antigen, du = dUTPase, pro = protease, pol = polymerase (reverse transcriptase and integrase), env = envelope, bel 1-3 (bel 1is also known as tas;the bel 2 reading frame overlaps with another one named bet), tax, rex, tat, rev, vpu, vif, nef and vprencode small additional proteins. The HERV-K Rec protein is also known as K-Rev. HERV-K rec is found in HERV-K type II proviruses, while np9 is encoded by HERV-K type I proviruses.[20] In spumavirus, either gag-pro or pro-polare encoded in the same translational reading frame. HTLV-1 and HTLV-2 can be transmitted sexually,[21][22] by blood to blood contact (e.g. by blood transfusion or sharing needles when using drugs)[23][24] and via breast feeding.[25] Two HTLVs are well established. HTLV-1 and HTLV-2 are both involved in actively spreading epidemics, affecting 15-20 million people worldwide.[26] HTLV-1 is the most clinically significant of the two: at least 500,000 of the individuals infected with HTLV-1 eventually develop an often rapidly fatal leukemia, while others will develop a debilitative myelopathy, and yet others will experience uveitis, infectious dermatitis, or another inflammatory disorder. HTLV-2 is associated with milder neurologic disorders and chronic pulmonary infections. In the United States, HTLV-1/2 seroprevalence rates among volunteer blood donors average 0.016 percent.[citation needed] No specific illnesses have yet been associated with HTLV-3 and HTLV-4. While there is no present licensed vaccine, there are many factors which make a vaccine against HTLV-1 feasible. The virus displays relatively low antigenic variability, natural immunity does occur in humans, and experimental vaccination using envelope antigens has been shown to be successful in animal models. Plasmid DNA vaccines elicit potent and protective immune responses in numerous small-animal models of infectious diseases. However, their immunogenicity in primates appears less potent. In the past two decades a large initiative has been put forth to understand the biological and pathogenic properties of the human T-cell lymphotropic virus type 1 (HTLV-1); this has ultimately led to the development of various experimental vaccination and therapeutic strategies to combat HTLV-1 infection. These strategies include the development of envelope glycoprotein derived B-cell epitopes for the induction of neutralizing antibodies, as well as a strategy to generate a multivalent cytotoxic T-lymphocyte (CTL) response against the HTLV-1 Tax antigen. A vaccine candidate that can elicit or boost anti-gp46 neutralizing antibody response may have a potential for prevention and therapy against HTLV-1 infection.[27] Potential treatments include prosultiamine, a vitamin B-1 derivative, which has been shown to reduce viral load and symptoms;[28]azacytidine, an anti-metabolite, which has been credited with the cure of a patient in Greece;[29] tenofovir disoproxil (TDF), a reverse-transcriptase inhibitor used for HIV; cepharanthine, an alkaloid from stephania cepharantha hayata;[30] and phosphonated carbocyclic 2'-oxa-3'aza nucleosides (PCOANs).[31] A newer formulation of TDF, called tenofovir alafenamide (TAF), also has promise as a treatment with less toxicity.

Human Immunodeficiency Virus (HIV)

The human immunodeficiency viruses (HIV) are two species of Lentivirus (a subgroup of retrovirus) that infect humans. Over time they cause acquired immunodeficiency syndrome (AIDS),[1][2] a condition in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Without treatment, average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype.[3] In most cases, HIV is a sexually transmitted infection and occurs by contact with or transfer of blood, pre-ejaculate, semen, and vaginal fluids. Research has shown (for both same-sex and opposite-sex couples) that HIV is untransmissable through condomless sexual intercourse if the HIV-positive partner has a consistently undetectable viral load.[4][5] Non-sexual transmission can occur from an infected mother to her infant during pregnancy, during childbirth by exposure to her blood or vaginal fluid, and through breast milk.[6][7][8][9] Within these bodily fluids, HIV is present as both free virus particles and virus within infected immune cells. HIV infects vital cells in the human immune system, such as helper T cells (specifically CD4+ T cells), macrophages, and dendritic cells.[10] HIV infection leads to low levels of CD4+ T cells through a number of mechanisms, including pyroptosis of abortively infected T cells,[11] apoptosis of uninfected bystander cells,[12] direct viral killing of infected cells, and killing of infected CD4+ T cells by CD8+ cytotoxic lymphocytes that recognize infected cells.[13]When CD4+ T cell numbers decline below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to opportunistic infections, leading to the development of AIDS. Contents 1Virology1.1Classification1.2Structure and genome1.3Tropism1.4Replication cycle1.5Spread within the body1.6Genetic variability 2Diagnosis 3Research 4Treatment and transmission 5History5.1Discovery5.2Origins 6See also 7References 8Further reading 9External links See also: Subtypes of HIV Comparison of HIV speciesSpeciesVirulenceInfectivityPrevalenceInferred originHIV-1HighHighGlobalCommon chimpanzeeHIV-2LowerLowWest AfricaSooty mangabey HIV is a member of the genus Lentivirus,[14] part of the family Retroviridae.[15] Lentiviruses have many morphologies and biological properties in common. Many species are infected by lentiviruses, which are characteristically responsible for long-duration illnesses with a long incubation period.[16] Lentiviruses are transmitted as single-stranded, positive-sense, enveloped RNA viruses. Upon entry into the target cell, the viral RNA genome is converted (reverse transcribed) into double-stranded DNA by a virally encoded enzyme, reverse transcriptase, that is transported along with the viral genome in the virus particle. The resulting viral DNA is then imported into the cell nucleus and integrated into the cellular DNA by a virally encoded enzyme, integrase, and host co-factors.[17] Once integrated, the virus may become latent, allowing the virus and its host cell to avoid detection by the immune system, for an indeterminate amount of time.[18] The HIV virus can remain dormant in the human body for up to ten years after primary infection; during this period the virus does not cause symptoms. Alternatively, the integrated viral DNA may be transcribed, producing new RNA genomes and viral proteins, using host cell resources, that are packaged and released from the cell as new virus particles that will begin the replication cycle anew. Two types of HIV have been characterized: HIV-1 and HIV-2. HIV-1 is the virus that was initially discovered and termed both lymphadenopathy associated virus (LAV) and human T-lymphotropic virus 3 (HTLV-III). HIV-1 is more virulent and more infective than HIV-2,[19] and is the cause of the majority of HIV infections globally. The lower infectivity of HIV-2, compared to HIV-1, implies that fewer of those exposed to HIV-2 will be infected per exposure. Due to its relatively poor capacity for transmission, HIV-2 is largely confined to West Africa.[20] Main article: Structure and genome of HIV Diagram of the HIV virion HIV is different in structure from other retroviruses. It is roughly spherical[21] with a diameter of about 120 nm, around 60 times smaller than a red blood cell.[22] It is composed of two copies of positive-sense single-stranded RNA that codes for the virus's nine genes enclosed by a conical capsid composed of 2,000 copies of the viral protein p24.[23] The single-stranded RNA is tightly bound to nucleocapsid proteins, p7, and enzymes needed for the development of the virion such as reverse transcriptase, proteases, ribonuclease and integrase. A matrix composed of the viral protein p17 surrounds the capsid ensuring the integrity of the virion particle.[23] This is, in turn, surrounded by the viral envelope, that is composed of the lipid bilayer taken from the membrane of a human host cell when the newly formed virus particle buds from the cell. The viral envelope contains proteins from the host cell and relatively few copies of the HIV Envelope protein,[23] which consists of a cap made of three molecules known as glycoprotein (gp) 120, and a stem consisting of three gp41molecules that anchor the structure into the viral envelope.[24][25] The Envelope protein, encoded by the HIV env gene, allows the virus to attach to target cells and fuse the viral envelope with the target cell's membrane releasing the viral contents into the cell and initiating the infectious cycle.[24] As the sole viral protein on the surface of the virus, the Envelope protein is a major target for HIV vaccine efforts.[26] Over half of the mass of the trimeric envelope spike is N-linked glycans. The density is high as the glycans shield the underlying viral protein from neutralisation by antibodies. This is one of the most densely glycosylated molecules known and the density is sufficiently high to prevent the normal maturation process of glycans during biogenesis in the endoplasmic and Golgi apparatus.[27][28] The majority of the glycans are therefore stalled as immature 'high-mannose' glycans not normally present on human glycoproteins that are secreted or present on a cell surface.[29] The unusual processing and high density means that almost all broadly neutralising antibodies that have so far been identified (from a subset of patients that have been infected for many months to years) bind to, or are adapted to cope with, these envelope glycans.[30] The molecular structure of the viral spike has now been determined by X-ray crystallography[31] and cryogenic electron microscopy.[32] These advances in structural biology were made possible due to the development of stable recombinant forms of the viral spike by the introduction of an intersubunit disulphide bond and an isoleucine to proline mutation (radical replacement of an amino acid) in gp41.[33] The so-called SOSIP trimers not only reproduce the antigenic properties of the native viral spike, but also display the same degree of immature glycans as presented on the native virus.[34] Recombinant trimeric viral spikes are promising vaccine candidates as they display less non-neutralising epitopes than recombinant monomeric gp120, which act to suppress the immune response to target epitopes.[35] Structure of the RNA genome of HIV-1 The RNA genome consists of at least seven structural landmarks (LTR, TAR, RRE, PE, SLIP, CRS, and INS), and nine genes (gag, pol, and env, tat, rev, nef, vif, vpr, vpu, and sometimes a tenth tev, which is a fusion of tat, env and rev), encoding 19 proteins. Three of these genes, gag, pol, and env, contain information needed to make the structural proteins for new virus particles.[23] For example, env codes for a protein called gp160 that is cut in two by a cellular protease to form gp120 and gp41. The six remaining genes, tat, rev, nef, vif, vpr, and vpu (or vpx in the case of HIV-2), are regulatory genes for proteins that control the ability of HIV to infect cells, produce new copies of virus (replicate), or cause disease.[23] The two tat proteins (p16 and p14) are transcriptional transactivators for the LTR promoter acting by binding the TAR RNA element. The TAR may also be processed into microRNAs that regulate the apoptosis genes ERCC1 and IER3.[36][37] The rev protein (p19) is involved in shuttling RNAs from the nucleus and the cytoplasm by binding to the RRE RNA element. The vif protein (p23) prevents the action of APOBEC3G (a cellular protein that deaminates cytidine to uridine in the single-stranded viral DNA and/or interferes with reverse transcription[38]). The vpr protein (p14) arrests cell division at G2/M. The nef protein (p27) down-regulates CD4 (the major viral receptor), as well as the MHC class I and class II molecules.[39][40][41] Nef also interacts with SH3 domains. The vpu protein (p16) influences the release of new virus particles from infected cells.[23] The ends of each strand of HIV RNA contain an RNA sequence called a long terminal repeat (LTR). Regions in the LTR act as switches to control production of new viruses and can be triggered by proteins from either HIV or the host cell. The Psi element is involved in viral genome packaging and recognized by gag and rev proteins. The SLIP element (TTTTTT) is involved in the frameshift in the gag-pol reading frame required to make functional pol.[23] Main article: HIV tropism Diagram of the immature and mature forms of HIV The term viral tropism refers to the cell types a virus infects. HIV can infect a variety of immune cells such as CD4+ T cells, macrophages, and microglial cells. HIV-1 entry to macrophages and CD4+ T cells is mediated through interaction of the virion envelope glycoproteins (gp120) with the CD4 molecule on the target cells' membrane and also with chemokine co-receptors.[24][42] Macrophage-tropic (M-tropic) strains of HIV-1, or non-syncytia-inducing strains (NSI; now called R5 viruses[43]) use the β-chemokine receptor, CCR5, for entry and are thus able to replicate in both macrophages and CD4+ T cells.[44] This CCR5 co-receptor is used by almost all primary HIV-1 isolates regardless of viral genetic subtype. Indeed, macrophages play a key role in several critical aspects of HIV infection. They appear to be the first cells infected by HIV and perhaps the source of HIV production when CD4+ cells become depleted in the patient. Macrophages and microglial cells are the cells infected by HIV in the central nervous system. In the tonsils and adenoids of HIV-infected patients, macrophages fuse into multinucleated giant cells that produce huge amounts of virus. T-tropic strains of HIV-1, or syncytia-inducing strains (SI; now called X4 viruses[43]) replicate in primary CD4+ T cells as well as in macrophages and use the α-chemokine receptor, CXCR4, for entry.[44][45][46] Dual-tropic HIV-1 strains are thought to be transitional strains of HIV-1 and thus are able to use both CCR5 and CXCR4 as co-receptors for viral entry. The α-chemokine SDF-1, a ligand for CXCR4, suppresses replication of T-tropic HIV-1 isolates. It does this by down-regulating the expression of CXCR4 on the surface of HIV target cells. M-tropic HIV-1 isolates that use only the CCR5 receptor are termed R5; those that use only CXCR4 are termed X4, and those that use both, X4R5. However, the use of co-receptors alone does not explain viral tropism, as not all R5 viruses are able to use CCR5 on macrophages for a productive infection[44] and HIV can also infect a subtype of myeloid dendritic cells,[47] which probably constitute a reservoir that maintains infection when CD4+ T cell numbers have declined to extremely low levels. Some people are resistant to certain strains of HIV.[48] For example, people with the CCR5-Δ32 mutation are resistant to infection by the R5 virus, as the mutation leaves HIV unable to bind to this co-receptor, reducing its ability to infect target cells. Sexual intercourse is the major mode of HIV transmission. Both X4 and R5 HIV are present in the seminal fluid, which enables the virus to be transmitted from a male to his sexual partner. The virions can then infect numerous cellular targets and disseminate into the whole organism. However, a selection process[further explanation needed] leads to a predominant transmission of the R5 virus through this pathway.[49][50][51] In patients infected with subtype B HIV-1, there is often a co-receptor switch in late-stage disease and T-tropic variants that can infect a variety of T cells through CXCR4.[52] These variants then replicate more aggressively with heightened virulence that causes rapid T cell depletion, immune system collapse, and opportunistic infections that mark the advent of AIDS.[53] Thus, during the course of infection, viral adaptation to the use of CXCR4 instead of CCR5 may be a key step in the progression to AIDS. A number of studies with subtype B-infected individuals have determined that between 40 and 50 percent of AIDS patients can harbour viruses of the SI and, it is presumed, the X4 phenotypes.[54][55] HIV-2 is much less pathogenic than HIV-1 and is restricted in its worldwide distribution to West Africa. The adoption of "accessory genes" by HIV-2 and its more promiscuous pattern of co-receptor usage (including CD4-independence) may assist the virus in its adaptation to avoid innate restriction factors present in host cells. Adaptation to use normal cellular machinery to enable transmission and productive infection has also aided the establishment of HIV-2 replication in humans. A survival strategy for any infectious agent is not to kill its host, but ultimately become a commensal organism. Having achieved a low pathogenicity, over time, variants that are more successful at transmission will be selected.[56] The HIV replication cycle Mechanism of viral entry: 1. Initial interaction between gp120 and CD4. 2. Conformational change in gp120 allows for secondary interaction with CCR5. 3. The distal tips of gp41 are inserted into the cellular membrane. 4. gp41 undergoes significant conformational change; folding in half and forming coiled-coils. This process pulls the viral and cellular membranes together, fusing them. The HIV virion enters macrophages and CD4+ T cells by the adsorption of glycoproteins on its surface to receptors on the target cell followed by fusion of the viral envelope with the target cell membrane and the release of the HIV capsid into the cell.[57][58] Entry to the cell begins through interaction of the trimeric envelope complex (gp160 spike) on the HIV viral envelope and both CD4 and a chemokine co-receptor (generally either CCR5 or CXCR4, but others are known to interact) on the target cell surface.[57][58] Gp120 binds to integrin α4β7 activating LFA-1, the central integrin involved in the establishment of virological synapses, which facilitate efficient cell-to-cell spreading of HIV-1.[59] The gp160 spike contains binding domains for both CD4 and chemokine receptors.[57][58] The first step in fusion involves the high-affinity attachment of the CD4 binding domains of gp120 to CD4. Once gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change, exposing the chemokine receptor binding domains of gp120 and allowing them to interact with the target chemokine receptor.[57][58] This allows for a more stable two-pronged attachment, which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane.[57][58] Repeat sequences in gp41, HR1, and HR2 then interact, causing the collapse of the extracellular portion of gp41 into a hairpin shape. This loop structure brings the virus and cell membranes close together, allowing fusion of the membranes and subsequent entry of the viral capsid.[57][58] After HIV has bound to the target cell, the HIV RNA and various enzymes, including reverse transcriptase, integrase, ribonuclease, and protease, are injected into the cell.[57][failed verification] During the microtubule-based transport to the nucleus, the viral single-strand RNA genome is transcribed into double-strand DNA, which is then integrated into a host chromosome. HIV can infect dendritic cells (DCs) by this CD4-CCR5 route, but another route using mannose-specific C-type lectin receptorssuch as DC-SIGN can also be used.[60] DCs are one of the first cells encountered by the virus during sexual transmission. They are currently thought to play an important role by transmitting HIV to T cells when the virus is captured in the mucosa by DCs.[60] The presence of FEZ-1, which occurs naturally in neurons, is believed to prevent the infection of cells by HIV.[61] Clathrin-mediated endocytosis HIV-1 entry, as well as entry of many other retroviruses, has long been believed to occur exclusively at the plasma membrane. More recently, however, productive infection by pH-independent, clathrin-mediated endocytosis of HIV-1 has also been reported and was recently suggested to constitute the only route of productive entry.[62][63][64][65][66] Reverse transcription of the HIV genome into double-stranded DNA Shortly after the viral capsid enters the cell, an enzyme called reverse transcriptase liberates the positive-sense single-stranded RNA genome from the attached viral proteins and copies it into a complementary DNA (cDNA) molecule.[67] The process of reverse transcription is extremely error-prone, and the resulting mutations may cause drug resistance or allow the virus to evade the body's immune system. The reverse transcriptase also has ribonuclease activity that degrades the viral RNA during the synthesis of cDNA, as well as DNA-dependent DNA polymerase activity that creates a sense DNA from the antisense cDNA.[68] Together, the cDNA and its complement form a double-stranded viral DNA that is then transported into the cell nucleus. The integration of the viral DNA into the host cell's genome is carried out by another viral enzyme called integrase.[67] The integrated viral DNA may then lie dormant, in the latent stage of HIV infection.[67] To actively produce the virus, certain cellular transcription factorsneed to be present, the most important of which is NF-κB (nuclear factor kappa B), which is upregulated when T cells become activated.[69] This means that those cells most likely to be targeted, entered and subsequently killed by HIV are those actively fighting infection. During viral replication, the integrated DNA provirus is transcribed into RNA, some of which then undergo RNA splicing to produce mature messenger RNAs(mRNAs). These mRNAs are exported from the nucleus into the cytoplasm, where they are translated into the regulatory proteins Tat (which encourages new virus production) and Rev. As the newly produced Rev protein is produced it moves to the nucleus, where it binds to full-length, unspliced copies of virus RNAs and allows them to leave the nucleus.[70] Some of these full-length RNAs function as new copies of the virus genome, while others function as mRNAs that are translated to produce the structural proteins Gag and Env. Gag proteins bind to copies of the virus RNA genome to package them into new virus particles.[71] HIV-1 and HIV-2 appear to package their RNA differently.[72][73] HIV-1 will bind to any appropriate RNA.[74] HIV-2 will preferentially bind to the mRNA that was used to create the Gag protein itself.[75] Further information: Genetic recombination Two RNA genomes are encapsidated in each HIV-1 particle (see Structure and genome of HIV). Upon infection and replication catalyzed by reverse transcriptase, recombination between the two genomes can occur.[76][77] Recombination occurs as the single-strand, positive-sense RNA genomes are reverse transcribed to form DNA. During reverse transcription, the nascent DNA can switch multiple times between the two copies of the viral RNA. This form of recombination is known as copy-choice. Recombination events may occur throughout the genome. Anywhere from two to 20 recombination events per genome may occur at each replication cycle, and these events can rapidly shuffle the genetic information that is transmitted from parental to progeny genomes.[77] Viral recombination produces genetic variation that likely contributes to the evolution of resistance to anti-retroviral therapy.[78] Recombination may also contribute, in principle, to overcoming the immune defenses of the host. Yet, for the adaptive advantages of genetic variation to be realized, the two viral genomes packaged in individual infecting virus particles need to have arisen from separate progenitor parental viruses of differing genetic constitution. It is unknown how often such mixed packaging occurs under natural conditions.[79] Bonhoeffer et al.[80] suggested that template switching by reverse transcriptase acts as a repair process to deal with breaks in the single-stranded RNA genome. In addition, Hu and Temin[76]suggested that recombination is an adaptation for repair of damage in the RNA genomes. Strand switching (copy-choice recombination) by reverse transcriptase could generate an undamaged copy of genomic DNA from two damaged single-stranded RNA genome copies. This view of the adaptive benefit of recombination in HIV could explain why each HIV particle contains two complete genomes, rather than one. Furthermore, the view that recombination is a repair process implies that the benefit of repair can occur at each replication cycle, and that this benefit can be realized whether or not the two genomes differ genetically. On the view that recombination in HIV is a repair process, the generation of recombinational variation would be a consequence, but not the cause of, the evolution of template switching.[80] HIV-1 infection causes chronic inflammation and production of reactive oxygen species.[81] Thus, the HIV genome may be vulnerable to oxidative damages, including breaks in the single-stranded RNA. For HIV, as well as for viruses in general, successful infection depends on overcoming host defensive strategies that often include production of genome-damaging reactive oxygen species. Thus, Michod et al.[82] suggested that recombination by viruses is an adaptation for repair of genome damages, and that recombinational variation is a byproduct that may provide a separate benefit. HIV assembling on the surface of an infected macrophage. The HIV virions have been marked with a green fluorescent tag and then viewed under a fluorescent microscope. The final step of the viral cycle, assembly of new HIV-1 virions, begins at the plasma membrane of the host cell. The Env polyprotein (gp160) goes through the endoplasmic reticulum and is transported to the Golgi apparatus where it is cleaved by furin resulting in the two HIV envelope glycoproteins, gp41 and gp120.[83] These are transported to the plasma membrane of the host cell where gp41 anchors gp120 to the membrane of the infected cell. The Gag (p55) and Gag-Pol (p160) polyproteins also associate with the inner surface of the plasma membrane along with the HIV genomic RNA as the forming virion begins to bud from the host cell. The budded virion is still immature as the gag polyproteins still need to be cleaved into the actual matrix, capsid and nucleocapsid proteins. This cleavage is mediated by the packaged viral protease and can be inhibited by antiretroviral drugs of the protease inhibitor class. The various structural components then assemble to produce a mature HIV virion.[84] Only mature virions are then able to infect another cell. Animation demonstrating cell-free spread of HIV. The classical process of infection of a cell by a virion can be called "cell-free spread" to distinguish it from a more recently recognized process called "cell-to-cell spread".[85] In cell-free spread (see figure), virus particles bud from an infected T cell, enter the blood or extracellular fluid and then infect another T cell following a chance encounter.[85] HIV can also disseminate by direct transmission from one cell to another by a process of cell-to-cell spread, for which two pathways have been described. Firstly, an infected T cell can transmit virus directly to a target T cell via a virological synapse.[59][86] Secondly, an antigen-presenting cell (APC), such as a macrophage or dendritic cell, can transmit HIV to T cells by a process that either involves productive infection (in the case of macrophages) or capture and transfer of virions in trans (in the case of dendritic cells).[87] Whichever pathway is used, infection by cell-to-cell transfer is reported to be much more efficient than cell-free virus spread.[88] A number of factors contribute to this increased efficiency, including polarised virus budding towards the site of cell-to-cell contact, close apposition of cells, which minimizes fluid-phase diffusion of virions, and clustering of HIV entry receptors on the target cell towards the contact zone.[86] Cell-to-cell spread is thought to be particularly important in lymphoid tissues where CD4+ T cells are densely packed and likely to interact frequently.[85] Intravital imaging studies have supported the concept of the HIV virological synapse in vivo.[89] The many spreading mechanisms available to HIV contribute to the virus' ongoing replication in spite of anti-retroviral therapies.[85][90] Further information: Subtypes of HIV The phylogenetic tree of the SIV and HIV HIV differs from many viruses in that it has very high genetic variability. This diversity is a result of its fast replication cycle, with the generation of about 1010virions every day, coupled with a high mutation rate of approximately 3 x 10−5 per nucleotide base per cycle of replication and recombinogenic properties of reverse transcriptase.[91][92][93] This complex scenario leads to the generation of many variants of HIV in a single infected patient in the course of one day.[91] This variability is compounded when a single cell is simultaneously infected by two or more different strains of HIV. When simultaneous infection occurs, the genome of progeny virions may be composed of RNA strands from two different strains. This hybrid virion then infects a new cell where it undergoes replication. As this happens, the reverse transcriptase, by jumping back and forth between the two different RNA templates, will generate a newly synthesized retroviral DNA sequence that is a recombinant between the two parental genomes.[91] This recombination is most obvious when it occurs between subtypes.[91] The closely related simian immunodeficiency virus (SIV) has evolved into many strains, classified by the natural host species. SIV strains of the African green monkey (SIVagm) and sooty mangabey (SIVsmm) are thought to have a long evolutionary history with their hosts. These hosts have adapted to the presence of the virus,[94] which is present at high levels in the host's blood, but evokes only a mild immune response,[95] does not cause the development of simian AIDS,[96] and does not undergo the extensive mutation and recombination typical of HIV infection in humans.[97] In contrast, when these strains infect species that have not adapted to SIV ("heterologous" or similar hosts such as rhesus or cynomologus macaques), the animals develop AIDS and the virus generates genetic diversity similar to what is seen in human HIV infection.[98] Chimpanzee SIV (SIVcpz), the closest genetic relative of HIV-1, is associated with increased mortality and AIDS-like symptoms in its natural host.[99] SIVcpz appears to have been transmitted relatively recently to chimpanzee and human populations, so their hosts have not yet adapted to the virus.[94] This virus has also lost a function of the nef gene that is present in most SIVs. For non-pathogenic SIV variants, nef suppresses T cell activation through the CD3 marker. Nef's function in non-pathogenic forms of SIV is to downregulate expression of inflammatory cytokines, MHC-1, and signals that affect T cell trafficking. In HIV-1 and SIVcpz, nef does not inhibit T-cell activation and it has lost this function. Without this function, T cell depletion is more likely, leading to immunodeficiency.[99][100] Three groups of HIV-1 have been identified on the basis of differences in the envelope (env) region: M, N, and O.[101] Group M is the most prevalent and is subdivided into eight subtypes (or clades), based on the whole genome, which are geographically distinct.[102] The most prevalent are subtypes B (found mainly in North America and Europe), A and D (found mainly in Africa), and C (found mainly in Africa and Asia); these subtypes form branches in the phylogenetic tree representing the lineage of the M group of HIV-1. Co-infection with distinct subtypes gives rise to circulating recombinant forms (CRFs). In 2000, the last year in which an analysis of global subtype prevalence was made, 47.2% of infections worldwide were of subtype C, 26.7% were of subtype A/CRF02_AG, 12.3% were of subtype B, 5.3% were of subtype D, 3.2% were of CRF_AE, and the remaining 5.3% were composed of other subtypes and CRFs.[103] Most HIV-1 research is focused on subtype B; few laboratories focus on the other subtypes.[104] The existence of a fourth group, "P", has been hypothesised based on a virus isolated in 2009.[105] The strain is apparently derived from gorilla SIV (SIVgor), first isolated from western lowland gorillas in 2006.[105] HIV-2's closest relative is SIVsm, a strain of SIV found in sooty mangabees. Since HIV-1 is derived from SIVcpz, and HIV-2 from SIVsm, the genetic sequence of HIV-2 is only partially homologous to HIV-1 and more closely resembles that of SIVsm.[citation needed][106] Main article: Diagnosis of HIV/AIDS A generalized graph of the relationship between HIV copies (viral load) and CD4 counts over the average course of untreated HIV infection; any particular individual's disease course may vary considerably. CD4+ T cell count (cells per µL) HIV RNA copies per mL of plasma Many HIV-positive people are unaware that they are infected with the virus.[107] For example, in 2001 less than 1% of the sexually active urban population in Africa had been tested, and this proportion is even lower in rural populations.[107] Furthermore, in 2001 only 0.5% of pregnant women attending urban health facilities were counselled, tested or receive their test results.[107] Again, this proportion is even lower in rural health facilities.[107] Since donors may therefore be unaware of their infection, donor blood and blood products used in medicine and medical research are routinely screened for HIV.[108] HIV-1 testing is initially done using an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to HIV-1. Specimens with a non-reactive result from the initial ELISA are considered HIV-negative, unless new exposure to an infected partner or partner of unknown HIV status has occurred. Specimens with a reactive ELISA result are retested in duplicate.[109] If the result of either duplicate test is reactive, the specimen is reported as repeatedly reactive and undergoes confirmatory testing with a more specific supplemental test (e.g., a polymerase chain reaction (PCR), western blot or, less commonly, an immunofluorescence assay (IFA)). Only specimens that are repeatedly reactive by ELISA and positive by IFA or PCR or reactive by western blot are considered HIV-positive and indicative of HIV infection. Specimens that are repeatedly ELISA-reactive occasionally provide an indeterminate western blot result, which may be either an incomplete antibody response to HIV in an infected person or nonspecific reactions in an uninfected person.[110] HIV deaths (other than U.S.) in 2014.[111] Nigeria (15.76%) South Africa (12.51%) India (11.50%) Tanzania (4.169%) Mozambique (4.061%) Zimbabwe (3.49%) Cameroon (3.09%) Indonesia (3.04%) Kenya (2.98%) Uganda (2.97%) Malawi (2.94%) DR Congo (2.17%) Ethiopia (2.11%) Other (29.21%) Although IFA can be used to confirm infection in these ambiguous cases, this assay is not widely used. In general, a second specimen should be collected more than a month later and retested for persons with indeterminate western blot results. Although much less commonly available, nucleic acid testing (e.g., viral RNA or proviral DNA amplification method) can also help diagnosis in certain situations.[109] In addition, a few tested specimens might provide inconclusive results because of a low quantity specimen. In these situations, a second specimen is collected and tested for HIV infection. Modern HIV testing is extremely accurate, when the window period is taken into consideration. A single screening test is correct more than 99% of the time.[112]The chance of a false-positive result in a standard two-step testing protocol is estimated to be about 1 in 250,000 in a low risk population.[113] Testing post-exposure is recommended immediately and then at six weeks, three months, and six months.[114] The latest recommendations of the US Centers for Disease Control and Prevention (CDC) show that HIV testing must start with an immunoassay combination test for HIV-1 and HIV-2 antibodies and p24 antigen. A negative result rules out HIV exposure, while a positive one must be followed by an HIV-1/2 antibody differentiation immunoassay to detect which antibodies are present. This gives rise to four possible scenarios: 1. HIV-1 (+) & HIV-2 (−): HIV-1 antibodies detected 2. HIV-1 (−) & HIV-2 (+): HIV-2 antibodies detected 3. HIV-1 (+) & HIV-2 (+): both HIV-1 and HIV-2 antibodies detected 4. HIV-1 (−) or indeterminate & HIV-2 (−): Nucleic acid test must be carried out to detect the acute infection of HIV-1 or its absence.[115]

Escherichia coli O157:H7

Toxin-producing strain of E. coli First seen in 1982 Leading cause of diarrhea worldwide

Hantavirus

Type of RNA virus. Hantavirus pulmonary syndrome and Korean hemorrhagic fever are caused by viruses in the genus Hantavirus.

Chlamydia pneumoniae

atypical pneumonia; association with coronary artery disease

Shigella dysenteriae causes

bacterial dysentery or shigellosis

Vibrio cholerae

causative agent of cholera

Bovine Spongiform Encephalopathy

disease of cattle ("mad cow disease") that can be transmitted to humans, causing Creutzfeldt-Jakob disease

Herpes simplex I and II

genital herpes: caused by the herpes simplex virus, leads to genital ulcers for both sexes, is recurrent.

Cytomegalovirus

herpes-type virus that usually causes disease when the immune system is compromised

Epstein Barr Virus

infectious mononucleosis

Mycobacterium leprae

leprosy (Hansen's disease)

Streptococcus pyogenes

strep throat

Francisella tularensis

tularemia (rabbit fever)