Microbiology- Viruses

Bornaviruses

(-) ss RNA; enveloped -somehow associated w/ Schizophrenia -first assoc w/ horse infections in Germany

Retrovirus accessory genes

*in HIV Tax/Tat- transactivation of viral & cellular genes Rex/Rev-regulation of RNA splicing and promotion of export to cytoplasm Vif- virus infectivity; promotion of virion assembly; blocks cellular antiviral protein Vpu- facilitates virion assemly and release

Coronavirus

+ sense ss RNA; ENVELOPED 2nd most common cause of common cold, after Rhinoviruses (Transmission: aerosols & large droplets) -cold viruses grow best at 33C (found in nose, not lungs) -E2 glycoproteins- assoc. w/ envelope spikes- responsible for mediating viral attachment to host cell and membrane fusion; target of neutralizing Abs -Can survive GI tract b/c of glycoprotein 'corona' SARS (Severe Acute Respiratory Syndrome)- in 2002 a coronavirus from animals crossed into humans and caused SARS; 1st natural outbreak in China. -Fever, non-productive cough, SOB, lower respiratory tract involvement (pneumonia); some pts become hypoxemic; 10-40% cases often require intubation and mechanical ventilation -Mortality ~10%, increases w/ age SARS CoV superspreading= transmission of virus to 8+ contacts; RFs for superspreading correlate w/ illness severity and older age -In 2004 & 2005, at least 2 new coronaviruses were isolated- HCoVNL63 (Netherlands), HCoV-NH (New Haven), and HCoVHKU1 (Hong Kong University)

Norovirus & Sapoviruses

+ sense ss RNA; NAKED CAPSID Resistant to drying, detergents, and acid Transmission: fecal-oral route in contaminated H2O and food. Causes outbreaks of gastroenteritis (dz resolves w/in 48 hours) Noroviruses (sp= Norwalk virus) and Sapoviruses (Sp= Sapporoviruses) part of family Calciviridae- both cause gastroenteritis (Noroviruses account for a large percentage of all viral outbreaks of gastroenteritis) Sapporoviruses & Sapporo-like viruses have a classical calcivirus surface morphology- cup shaped indentations and 6-point star shape). Noroviruses have a different morphology- round w/ ragged surface Norovirus genomes have 3 open reading frames; Sapporoviruses have 2.

Hepatitis D

Very small RNA genome- single-stranded RNA is circular and forms a rod shape as a result of its extensive base pairing Genome is surrounded by the delta antigen core, which is surrounded by an HBsAg-containing envelope Replication: host cell's RNA polymerase II makes an RNA copy to replicate the genome. The genome then forms an RNA structure called a ribozyme, which cleaves the RNA circle to produce an mRNA for the small delta antigen. The gene for the delta antigen is mutated by a cellular enzyme during infection, thereby allowing production of large quantities of the large delta antigen. Production of this antigen limits replication of the virus but also promotes association of the genome with HBsAg to form a virion, and the virus is then released from the cell. Can replicate and cause disease only in people with active HBV infections More rapid, severe progression occurs in HBV carriers superinfected with HDV than in people coinfected with HBV and the delta agent, because during coinfection HBV must first establish its infection before HDV can replicate, whereas superinfection of an HBV-infected person allows the delta agent to replicate immediately. Replication of the delta agent results in cytotoxicity and liver damage. Unlike HBV disease, damage to the liver occurs as a result of the direct cytopathic effect of the delta agent combined with the underlying immunopathology of the HBV disease. Delta agent increases the severity of HBV infections. Fulminant hepatitis is more likely to develop in people infected with the delta agent than in those infected with the other hepatitis viruses. Fulminant hepatitis causes altered brain function (hepatic encephalopathy), extensive jaundice, and massive hepatic necrosis. Dx: detect the RNA genome, the delta antigen, or anti-HDV antibodies. Use ELISA, radioimmunoassays, or RT-PCR No known tx. Prevention of HBV infection prevents HDV infection. Immunization with HBV vaccine protects against subsequent deltavirus infection.

Reovirus replication

Virus ingested- virion outer capsid protects inner nucleocapsid and core from the environment, esp gastric acid --> complete virion partially digested in GI tract and activated by protease cleavage and loss of external capsid proteins to produce ISVP (intermediate/infectious subviral particles) ISVP releases core into cytoplasm--> enzymes in core initiate mRNA production. *The double stranded RNA always remains in the core* In a manner similar to a negative-sense RNA virus, each of the negative sens RNA strands is used as a template by virion core enzymes, which synthesize individual mRNAs. Virion enzymes w/in core add 5' cap and 3' tail --> mRNA leaves core and is translated. Later, virion proteins and +sense RNA segments associate together into core-like structures that aggregate into large cytoplasmic inclusions. The + RNA segments are copied to produce - RNA, replicating the double stranded genome. The new cores either generate more + RNA or are assembled into virions. Virus released by cell lysis *What's unique about the reovirus transcription system is that transcription takes place within the viral core- the double-stranded RNA templates used for synthesis of mRNA NEVER LEAVE THE CORE OF THE VIRUS

Colorado tick fever

caused by Coltivirus (a reovirus) Transmission: WOOD TICK (Dermancentor andersoni)- zoonotic dz; occurs mainly in spring, summer, and fall in Western US. Produces a maculopapular/petechial rash- must be distinguished from rash of Rocky Mountain Spotted fever, which is also tick borne (Rickettsiae; Rocky Mtn Spotted fever is more serious) Initial symptoms include fever, chills, headaches, pain behind the eyes, light sensitivity, muscle pain, generalized malaise, abdominal pain, nausea, and vomiting, as well as a flat or pimply rash Coltivirus infects mainly erythroid precursor cells w/out severely damaging them- remains w/in cells, even after they mature to RBCs --> protected from viral clearance. Resulting viremia can persist for weeks-months, even after recovery from Sx. --> Both of these factors promote transmission. Serious hemorrhagic disease can result from infection of vascular endothelial SMCs and pericytes, weakening the capillary structure--> leakage, hemorrhage, potential hypotension and shock

Rhabdovirus

- sense ss RNA virus; ENVELOPED; BULLET SHAPED -simple genome, encodes 5 proteins; Spikes (timers of Glycoprotein G) cover the surface and generate neutralizing Abs. virus buds through plasma membrane; cell death and lysis occur after infection w/ most Rhabdoviruses EXCEPT Rabies virus (produces v. little cell damage) Rabies Virus- transmitted in SALIVA- acquired from bite of rabid animal; virus replicates in muscle at site of bite, w/ minimal/no Sx (incubation phase). Length of incubation phase determined by infectious dose and proximity of infection site to CNS and brain. After weeks-months, virus infects peripheral nerves and travels up to CNS (prodrome phase). During this phase, virus spreads to glands, skin, etc, from which its spread. Infection of brain causes classic Sx, coma, and death Rabies infection doesn't elicit Ab response until late stages of Dz, when virus has spread from CNS to other sites. Ab can block progression of virus & Dz. *Long incubation period allows active immunization as a post-exposure treatment. -Virus induces aggressive behavior in animals- promotes virus spread. Source: saliva in bite of rabid animal; aerosols in bat caves containing rabid bats. Post-exposure prophylaxis: local treatment of wound (wash immediately w/ soap and water) --> immunize victim w/ 1 dose of human rabies Ig or equine antirabies serum- this passive immunization provides Ab until pt produces Ab in response to vaccine. A series of immunizations is then administered over the course of a month NEGRI BODIES-clinical evidence of infection doesn't occur until late --> Dx of rabies made through detection of viral antigen in CNS or skin, virus isolation, genome detection, and serologic findings. Hallmark diagnostic finding- intra-cytoplasmic inclusions consisting of aggregates of viral nucleocapsids in affected neurons. *Although diagnostic, only seen in 70-90% of brain tissue from infected humans.

Transcription Based Amplification

-Uses RT & viral sequence-specific primers to make cDNA that has a sequence recognized by DNA-dependent RNA Pol of the T7 bacteriophage -RNA digested w/ RNAse H--> RNA converted to cDNA--> DNA transcribed to RNA by T7 bacteriophage's DNA-dependent RNA Pol --> new RNA sequences cycled back into reaction to amplify relevant sequence -Unlike PCR, doesn't require special equipment w/ cycles of heating, cooling, etc. *In this you're not replicating DNA, just RNA

5 childhood exanthemas

-Varicella (HHV-3/VZV) -Rubella (Togaviridae) -Roseola (HHV-6/HHV-7) -Measles (Paramyxoviridae)- AKA RUBEOLA -B19- AKA 5TH DZ, SLAPPED CHEEK SYNDROME, EXANTHEMA INFECTIOSUM

Measles

-caused by paramyxovirus (ss - sense RNA virus); enveloped AKA RUBEOLA Highly contagious; transmitted from person to person by respiratory droplets. Local replication of virus in the respiratory tract --> spread to the lymphatic system and cell-associated viremia. The wide dissemination of the virus causes infection of the conjunctiva, respiratory tract, urinary tract, small blood vessels, lymphatic system, and the central nervous system. Prodrome- high fevers, CCC+P (cough, conjunctivitis, coryza, photophobia); KOPLIK'S SPOTS (develop ~2 days before rash- white spots on mucous membranes- mouth, vagina; described as grains of salt surrounded by a red halo; appearance in mouth establishes the dx of measles w/ certainty) --> Rash- maculopapular; spreads downward from forehead to feet; fades in the same order it appeared. Fever is highest and pt is sickest the day the rash appears (caused by immune T cells targeted to measles-infected endothelial cells lining small blood vessels) SUBACUTE SCLEROSING PANENCEPHALITIS- extremely serious, very late neurologic sequela of measles; occurs when a defective measles virus persists in the brain and acts as a slow virus. The virus can replicate and spread directly from cell to cell but is not released. . SSPE is most prevalent in children who were initially infected when <2 years and occurs ~7 years after clinical measles. The patient demonstrates changes in personality, behavior, and memory, followed by myoclonic jerks, blindness, and spasticity. Unusually high levels of measles antibodies are found in the blood and CSF of patients with SSPE. *MMR Vaccine

Respiratory Syncytial virus

-caused by paramyxovirus (ss - sense RNA virus); enveloped; lacks both NA & HA (in contrast to other paramyxoviruses) Can cause any respiratory tract illness, from a common cold to pneumonia. Upper respiratory tract infection with prominent rhinorrhea (runny nose) is most common in older children and adults. A more severe lower respiratory tract illness, bronchiolitis, may occur in infants Patient usually has low-grade fever, tachypnea, tachycardia, and expiratory wheezes over the lungs. Bronchiolitis is usually self-limited, but it can be a frightening disease to observe in an infant. It may be fatal in premature infants, persons with underlying lung disease, and immunocompromised people. There is no vaccine for RSV. Ribavirin= antiviral compound approved for use of severe RSV infections. Used in aerosol form, for infants with serious disease

HHV-3 (VZV)

Varicella (chickenpox)- normally symptomatic- fever + maculopapular rash; each maculopapular lesion forms a thin-walled vesicle on an erythematous base- vesicle becomes pustular and crusts w/in 12 hrs Zoster (shingles)- recurrence of a latent varicella infxn; usually preceded by severe pain in area innervated by nerve prior to appearance of chickenpox-like lesions; rash usually limited to 1 dermatome *live vaccine for Varicella zoster

Clinical Hepatitis B

Acute infection- kids less severe than adults; long incubation period w/ insidious onset. Prodromal symptoms include fever, malaise, nausea and vomiting, abdominal pain, chills. Jaundice follows soon after. Recovery- decreased fever and increased apetite. RASH, polyarthritis, fever, vasculitis, and glomerulitis are complications of IMMUNE COMPLEX formation. Chronic Infection- occurs in 10-15% pts; 1/3 of these pts will have cirrhosis. These pts are a major source of viral spread. Primary hepatocellular carcinoma- 80% of PHC can be attributed to HBV infxn, the genome is integrated into these cells, and the cells express the HB antigens. HBV may induce PHC by promoting continued liver repair and cell growth in response to tissue damage or by integrating into the host Cs and stimulating cell growth directly Dx: initially Dx based on clinical symptoms, ↑ liver enzymes. HBsAg and HBeAg are secreted into the blood during viral replication. Presence of HBeAg is the best correlate to the presence of infective virus. A chronic infection can be distinguished by the continued finding of HBeAg, HBsAg, or both AND a lack of detectable Ab to these Ags. During the symptomatic phase antibodies to HBeAg and HBsAg are obscured because the Ab is complexed with the Ag in the serum. The best way to dx a recent infection is to measure IgM v. HBc

Other drugs for Hep B

Adefovir/Dipivoxil- nucleoTide analog RT inhibitors Entecavir, Telbivudine- nucleoSide analog RT inhibitors Laboratory evidence for the suppression of viral replication involves: o A reduction in HBe-Ag expression o Seroconversion to anti-HBe o Loss/reduction in viral load Line Probe Assay (LiPA)- commercial test for the detection of mutations in the gene that codes for the pol/RT protein. Viral DNA is amplified by PCR --> pol/RT amplicons hybridized to LiPA strips containing probes (nucleic acid sequences) for wild type pol/RT and mutant pol/RT.

Non-nucleotide analog RT inhibitors (NNRTIs)

Allosteric inhibitors of RT o Nevirapine o Delavirdine

Influenza Drugs

Amantidine & Rimantidine- diminishes duration and severity of disease; most effective when given prophylactically. It is usually given to elderly institutionalized individuals and to patients with cardiopulmonary compromise during a community epidemic of Influenza A. MOA- prevents viral uncoating by interacting with the membrane (M2) protein that forms a H+ channel in the host cell's membrane and facilitates uncoating (without the influx of H+, M1 proteins don't dissociate from nucleocapsid [uncoating]). (Rimantadine has fewer SEs) *M1 proteins: line the inside of the virion; promote assembly M2 proteins: form a proton channel in membranes; promotes uncoating and viral release (changes in M2 protein prob. assoc w/ resistance to Amantidine/Rimantidine) Zamamivir & Osteltamivir- NA inhibitors; effective v. Influenza A & B (not C b/c C doesn't have NA). Newer agents. *Cross-resistance against Tamiflu to other neuraminidase inhibitors (zanamivir) occurs. Drug resistance against Tamiflu has been associated with amino acid changes in the neuraminidase or hemagglutinin or both. Nucleoside analogue Ribavirin is active against both influenza A and B.

RT-PCR

Amplifies and simultaneously quantifies a targeted DNA molecule. Its key feature is that the amplified DNA is detected as the reaction progresses in real time. Two common methods for detection of products in real-time PCR are: (1) non-specific fluorescent dyes that intercalate with any double-stranded DNA, and (2) sequence-specific DNA probes consisting of oligonucleotides that are labeled with a fluorescent reporter which permits detection only after hybridization of the probe with its complementary DNA target. Useful for detecting: -Latent & integrated sequences of viruses (retroviruses, herpesviruses, papillomaviruses) -Viruses present in low concentrations -Viruses that are difficult/dangerous to isolate in cell culture -Quantification of the amount of HIV w/in a pt (virus load)- concentration of HIV genome in blood proportional to rate of PCR amplification of genomic DNA

Antigenic drift & shift

Antigenic drift- replication errors leading to small changes in antigenic derminants of HA & NA; previously-formed Abs unable to completely prevent dz--> mild illness. This process occurs every 2-3 years, causing local outbreaks of influenza A and B infection (epidemics) (minor antigenic change *Influenza B can only undergo minor change) Antigenic shift- occurs when 2 Influenza A (only influenza A) viruses co-infect cell, trading of RNA segments btwn animal & human strains --> RNA segments mispackaged, leading to completely new hybrid viruses w/ NA and HA that no immune system has encountered [genomic segments to randomly associate into new virions] (major antigenic change)- leads to global pandemics

Lymphocytic Choriomeningitis

Arenavirus; virus has same name; Usually causes febrile illness w/ flulike myalgia. Only 10% of infected pts exhibit clinical evidence of a CNS infection. The meningeal illness, if it occurs, will start 10 days after the initial phase of illness, w/ full recovery. Hamsters and house mice are reservoirs. Mechanism of spread- contact w/ pet hamsters and animals in rodent-breeding facilities. ~20% of mice in Washington, DC have it!

HHV-8

Associated w/: Kaposi's sarcoma Multicentric Castleman's disease Body-cavity-based primary effusion lymphoma

Flavivirus

ENVELOPED; ss + sense RNA Flavivirus, Pestivirus, HEPACIVIRUS (HEP C) Most are arboviruses- acquired from bite of arthropod (mosquito) Diseases: DENGUE, YELLOW FEVER, Japanese encephalitis, WEST NILE ENCEPHALITIS, St. Louis encephalitis, Russian spring-summer encephalitis, Powassan encephalitis *Dengue and yellow fever viruses cause hemorrhagic fever and shock. Dengue (aka break bone fever)- HA, fever, rash, back and bone pain. When rechallenged w/ another of the 4 related strains, it can cause dengue shock syndrome- non-neutralizing Abs promote uptake of virus into MOs --> memory T cells become activated and release cytokines that initiate hypersensitivity rxn --> weakening and rupture of vasculature, internal bleeding, loss of plasma, and shock. Yellow fever- severe systemic disease w/ degeneration of liver, kidney, and heart, as well as hemorrhage. Liver problems- jaundice; massive GI hemorrage may occur (black vomit)

Avian influenza

Bird flu is H5N1; it is a concern because it might recombine with human flus to cause a super-flu and a pandemic. It is unique because it is not a reassortment, it is very virulent, and it passed directly from bird to man. Reassortment with a human influenza virus might generate a pandemic. Certain Asiatic regions are thought to be a breeding ground for many of the pandemic strains of influenza. Because of its high population density and proximity of humans, pigs, chickens, and ducks, China is thought to be a breeding ground for new reassortant viruses and the source of many of the pandemic strains of influenza. Avian influenza is transmitted in bird feces and not by human-to-human transmission. Since 1997, tens of millions of chickens have either died or have been killed because of various avian influenza virus subtypes. The subtypes involved have been H5N2 (1997, Hong Kong), H9N2 (1999-2000, S.E. Asia), H5N1 (2003, Hong Kong), H7N7 (2003, Netherlands) and H5N1 (2004-2005, S.E. Asia). Many of these subtypes have led to direct transmission from birds to humans with numerous deaths in humans. Fortunately, transmission of avian subtypes among humans has been rare and inefficient. If any of these subtypes mutate to permit transmission from person-to-person and also cause serious disease, then a pandemic may occur. The bird flu HA subtypes that have been prominent in poultry are H5, H7 and H9. Bird flu subtypes H5 and H7 have resulted in lethal human infections.

Pleconaril

Blocks uncoating of PICORNAVIRUSES; fits into a cleft in the receptor-binding region of capsid and prevents disassembly of capsid- inhibits key steps of penetration and uncoating, which are required to deliver viral genome into cytoplasm of host cell.

Mumps

Caused by paramyxovirus (ss - sense RNA virus); enveloped Virus replicates in upper respiratory tract and lymph nodes --> spreads via blood to distant organs. Parotid gland=most frequently involved organ- swells and becomes painful ~3 weeks after exposure; orchitis, meningitis can also occur MMR Vaccine In 2006, more than 2,500 cases of mumps were reported in the USA. Generally less than 300 cases are reported yearly. Young adults, ages 18-24 (college students), have accounted for most of those affected. Evidence suggests that mumps virus has been transmitted among individuals traveling on commercial airlines. The resurgence of mumps in the USA may be due to the use of only one dose of vaccine instead of two doses.

Parainfluenza virus

Caused by paramyxovirus (ss - sense RNA virus); enveloped causes URIs in adults; may cause pneumonia in children, elderly, immunocompromised CROUP- laryngotracheobronchitis in kids. results in subglottal swelling, which may close the airway. Hoarseness, a "seal bark" cough, tachypnea, tachycardia, and suprasternal retraction develop in infected patients after a 2-6 day incubation period. Most kids recover within 48 hours. DDx is epiglottitis caused by H. influenzae

Nucleotide-Analog Reverse Transcriptase Inhibitors (NRTIs)

Competitive inhibitors for RT o AZT (Azidothymidine, Zidovudine) o Dideocycytidine o Dideoxyinosine o Lamivudine

Herpesvirus

DS linear DNA; large, enveloped icosahedral capsids *encodes its own DNA Pol (target for drugs, e.g. Acyclovir) HSV-1 binds to cells through an initial interaction w/ HEPARAN SULFATE- proteoglycan found on the outside of many cell types -->tighter interactions w/ receptor proteins at cell surface. Penetration into cells requires interaction w/ NECTIN-1ALPHA- penetration via fusion of envelope w/ host cell membrane *Capsid proteins & DNA assembled in nucleus --> acquire envelope at nuclear or golgi membrane --> exit cell by lysis or exocytosis Transcription of viral genome occurs in 3 phases: Immediate early proteins- proteins important for regulation of transcription & takeover of cell Early proteins- TFs and Enzymes, inc. DNA POL & THYMIDINE KINASE Late proteins- structural proteins (often synthesis of late viral proteins signals events that lead to cell lysis --> if late proteins were synthesized at the same time as early proteins, empty viral capsids may be produced- haven't had a chance to assemble prior to lysis) Causes lytic (in most cells; COWDRY BODIES), persistent (in lymphocytes and MOs), latent (in neurons), and immortalizing (Epstein Barr) infxns. *In neurons, virus replicates in cells at base of lesion and infects innervating neuron --> travels by retrograde transport to ganglion --> recurrent infection of dermatome can be activated by stimuli such as stress, trauma, fever, sunlight- trigger viral replication in nerve cell --> virus travels down nerve to cause lesions at same dermatome Latent Infxn: EBV- B cells HSV-1/2- neurons VZV- DRG/Cranial nerve ganglia Sexually transmitted herpesviruses: HSV-2 & CMV (HHV-5) Herpesviruses assoc w/ malignancy: EBV (HHV-4) and HHV-8 (Kaposi's sarcoma)

Togavirus (Alphavirus)

ENVELOPED; ss + sense RNA Alphavirus, RUBIVIRUS (RUBELLA), arterivirus (no human disease) Most are arboviruses- acquired from bite of arthropod (mosquito). Humans= dead end hosts for togaviruses and flaviviruses- cannot spread virus back to vector b/c don't maintain persistent viremia. If virus not in blood, mosquito can't acquire it. Diseases: Sindbis, Semliki Forest, Venezuelan equine encephalitis, Eastern equine encepalitis, Western equine encephalitis, Chikungunya Major differences between togaviruses & flaviviruses: togaviruses bud at plasma membrane, flaviviruses bud at internal cytoplasmic vesicles; togavirus has a polyA tail at the 3' end, flavivirus doesn't; togaviruses encode early and late proteins, while flavivirus genomes are translated in a single polyprotein, like picornaviruses *Rubella virus differs from other togaviruses; unlike other togaviruses, rubella is a respiratory virus and doesn't caus readily detectable cytopathologic effects. Rubella infects upper respiratory tract --> spreads to local lymph nodes (lymphadenopathy)--> establishes viremia and causes a characteristic mild maculopapular rash. Common name= German measles -Rubella is one of 5 classic childhood exanthemas: Measles (paramyxoviridae); Chicken pox (VZV/HHV3); Roseola (HHV6/7); 5th Disease (parvovirus B19).

Bunyaviridae

ENVELOPED; ss - sense RNA; 3 RNA genome segments (L, M, S) - RNA nucleocapsis but no matrix proteins zoonotic; most bunyaviridae are arboviruses; virus in arthropod can be transmitted to its eggs; many cause encephalitis or hemorrhagic disease Disease mechanism: virus acquired from arthropod bite (e.g mosquito) --> initial viremia may cause flu-like Sx --> establishment of secondary viremia may allow virus access to specific target tissues, inc. CNS, organs, vascular endothelium. Antibody important in controlling viremia; interferon and cell-mediated immunity may prevent outgrowth of infection. Virus can pass into ovary and infect arthropod eggs, allowing it to survive in the winter. Hantavirus different from other bunyaviridae b/c it's carried by RODENTS (other bunyaviridae carried by mosquitoes, ticks, fleas). Virus in rat URINE transmitted to humans. Hantavirus endemic in Korea- illness called Korean hemorragic fever/hemorrhagic fever w/ renal syndrome (HFRS). Sx: high fever, severe HA, myalgia, vomiting, severe renal failure, hemorrhage. Most hantavirus infections in Asia and Europe. Hantavirus pulmonary syndrome (HPS)- different hantavirus serotype than HFRS caused outbreak of illness in Southwestern US. Less kidney involvement, but pulmonary edema common. Reservoirs= deer mice, some house and field mice, and other rodent species. Californa Encephalitis virus (La Crosse virus)- cause of viral encephalitis in Ohio, Wisconsin, Minnesota, etc. Spread by Aedes mosquitoes found in the forests of N. America- lay eggs in small pools of water trapped in places like trees and tires. People at risk: campers, forest rangers, woodsmen

Arenaviridae

ENVELOPED; ss RNA; 2 circular - sense RNA genome segments (L, S). S genome segment is ambisense. zoonotic infections; persistent infections established in rodents. Pathogenesis of arenaviruses largely attributed to T-cell immunopathogenesis. LASSA, Junin, Machupo viruses= hemorrhagic arenaviruses that infect humans. Most arenaviruses (except virus that causes LCM) found in tropics of Africa and S. America- chronic asymptomatic infection in rodents --> chronic viremia & long-term viral shedding in saliva, urine, and feces. Humans may become infected through inhalation of aerosols, consumption of contaminated food, or contact w/ fomites. Bites are not a usual mechanism of spread.

Hepatitis C

FLAVIVIRDAE; + sense ss RNA; enveloped HCV coats itself with LDL or VLDL and then uses their receptor for uptake into hepatocytes Genome encodes proteins that undergo variation during infection because of hypervariable regions within their genes. HCV proteins inhibit apoptosis and TNF-a action by binding to the tumor necrosis factor receptor and to protein kinase R. These actions prevent the death of the host cell and promote persistent infection. HCV is transmitted primarily in infected blood and sexually. IV drug abusers, transfusion and organ recipients, and hemophiliacs are at highest risk for infection. HCV is especially prevalent in southern Italy, Spain, central Europe, Japan, and parts of the Middle East. The high incidence of chronic asymptomatic infections promotes the spread of the virus in the population. Causes 3 types of disease: acute hepatitis w/ resolution and recovery (15%); chronic persistent infection w/ progression to disease later in life (70%); severe and rapid progression to cirrhosis (15%) Dx- based on ELISA/Western blot recognition of HCV Ab or RNA genome (seroconversion takes 7-31 weeks); RT-PCR can detect RNA before (RT-PCR and related assays can also be used to follow antiviral treatments) Tx- recombinant INF-a or pegylated interferon, alone or with ribavarin

Basic Retroviral proteins

Gag- group-specific antigen. Includes proteins for: capsid, matrix and nucleic acid binding proteins Pol-polymerase, protease, integrase Env-envelope glycoproteins *The basic gene set that allows the virus to replicate is pol, since it encodes the reverse transcriptase in addition to the polymerases

Ribavirin

Guanosine analog; must be phosphorylated (like other nucleoside analogs); active v. a broad range of viruses MOAs: -Inhibits nucleoside biosynthesis- inhibits Inosine Monophosphate Dehydrogenase (used in synthesis of Guanosine)- depletes guanosine stores -Prevents synthesis of 5' mRNA cap by interfering w/ guanylation and methylation of nucleic acid base -Inhibits RNA Polymerase, promotes hypermutation of genome -It's multiple MOAs may explain lack of Ribavirin-resistant mutants of RSV & Influenza A

Lamivudine

HIV drug; nucleoside RT inhibitor. Suppresses HBV DNA to undetectable levels. When using lamivudine, as many as 30% of the patients can have virus breakthrough (viral resistance) within one year or less of treatment. Mutations involved with the viral polymerase-pol/reverse transcriptase-RT are associated with resistance

Hepatitis B

Hepadnavirus- ENVELOPED DNA virus (small, circular, PARTLY DOUBLE STRANDED-stranded DNA) *Encodes REVERSE TRANSCRIPTASE- replicates through RNA intermediate. Virion (aka DANE PARTICLE) unusually stable for enveloped virus- resists treatment with ether, low pH, freezing, and moderate heating. Virion includes a protein kinase and a polymerase with reverse transcriptase and ribonuclease H activity, and a P protein attached to the genome, all of which is surrounded by the hepatitis B core antigen (HBcAg) and an envelope containing the glycoprotein hepatitis B surface antigen (HBsAg- originally called AUSTRALIA ANTIGEN). A hepatitis B e antigen (HBeAg) protein is a minor component of the virion (cleavage product of core protein- released during active infection). HBsAg (Australia antigen) includes 3 glycoproteins- L, M, S (the S glycoprotein is the major component of HBsAg particles) There are at least eight HBV genotypes (A-H). A genotype is based upon a 8% difference in complete nucleotide sequence information between genotypes Replication: (Viral DNA not replicated- new DNA made via mRNA and RT). Once in cell, partial DNA strand of the genome is completed → genome enters nucleus → DNA is transcribed by cellular elements into an mRNA that is bigger than the DNA → the mRNA goes to the cytoplasm → translated into proteins AND RT makes DNA from the giant mRNA (*Reverse transcription in the cytosol leads to genetic variability) Pathogenesis: Symptoms are caused by cell-mediated immunity (CMI) and immune complexes between antibody and hepatitis B surface antigen (HBsAg); can have acute, chronic or asymptomatic dz, depending on person's immune response. HBV infects the liver but does not cause direct cytopathology. Cell-mediated immune lysis of infected cells produces the symptoms and resolves the infection. Insufficient immunity can lead to chronic disease.

HAART

Highly active antiretroviral treatment= A cocktail of several antiviral drugs, each with different mechanisms of action- has less potential to breed resistance; recommended

Paramyxoviruses

Includes Parainfluenza virus (Parainfluenza virus and Mumps viruses), Pneumovirus (RSV), Morbillivirus (Measles virus) enveloped, ss - sense RNA Genome; In parainfluenza and mumps virus, HA and NA part of same glycoprotein spike; measles virus only has HA; RSV has neither HA nor NA Envelope has F protein- induces cell-cell fusion (syncytia formation and multinucleated giant cells) --> virus can pass directly from cell to cell and escape antibody control. M protein= matrix protein; lines the inside of the virion envelope and associates with the nucleocapsid. The M protein separates the capsid and the envelope Replicates in cytoplasm; transmission: Respiratory droplets A new group of highly pathogenic paramyxoviruses, including two zoonosis-causing viruses, Nipah virus and Hendra virus, was identified in 1998 after an outbreak of severe encephalitis in Malaysia and Singapore.

HHV-4 (Epstein-Barr)

Infectious Mononucleosis- much milder (usually subclinical) in children than adults (like all herpesvirus infxns) -Lymphadenopathy, hepatosplenomegaly, exudative pharyngitis, high fever, malaise, fatigue. Can cause serious complications resulting from neuro d/os, laryngeal obstruction, or rupture of spleen. Neuro complications: meningoencephalitis, Guillain Barre *Infectious mono= host immune response involves cytotoxic (CD8+) T cells against infected B lymphocytes, resulting in enlarged, atypical T lymphocytes (Downey cells)- increase in number in peripheral blood during 2nd week of infection; account for 10-80% of total WBC count at this time African Burkitt's Lymphoma -poorly differentiated monoclonal B cell lymphoma of jaw and face thats endemic in kids living in malarial regions of Africa.

Fusion Inhibitors

Inhibit fusion by blocking gp41 o Enfuvirtide

Filoviruses

Marburg & Ebolaviruses- cause dz in humans; potential terrorism agents. -cause severe and fatal hemorrhagic fevers; endemic in Africa. Illness begins w/ flu-like Sx, nausea, vomiting, and diarrhea --> hemorrhage from multiple sites (esp. GI tract) --> death

Hepatitis E

NOROVIRUS; naked capsid; + sense ss RNA Transmission: fecal-oral route; most problematic in developing countries Similar to Hep A; causes only acute disease The mortality rate associated with HEV disease is 1-2% (10x that associated with HAV). HEV infection is especially serious in pregnant women (mortality ~20%).

Phosphonoacetic acid & Phosphonoformic acid (Foscarnet)

Non-nucleoside polymerase inhibitors; inhibit Herpesvirus DNA polymerase by the pyrophosphate portion of nucleotide triphosphates. Bind to pyrophosphate-binding site of DNA Pol and inhibit viral replication. *Unlike Acyclovir & Ganciclovir, foscarnet not activated by viral protein kinases

Acyclovir

Nucleoside (Guanosine) analog; Inhibits viral DNA Polymerase (competes w/ GTP- causes termination of growing viral DNA chain b/c there's no 3'-OH group to allow chain elongation). Activated by phosphorylation by viral thymidine kinase (selective action against HSV & Varicella Zoster virus, b/c they encode thymidine kinase) -inhibits HSV replication, but can't resolve latent infection

HHV-5 (Cytomegalovirus)

Opportunistic; rarely causes Sx in non-immunocompromised pts, but serious dz in pts w/ AIDS, neonates, etc. CMV dz of lungs- pneumonia & pneumonitis- common outcome in immunosuppressed pts; can be fatal if untreated; often causes retinitis in severely immunodeficient pt In neonates- microcephaly, hepatosplenomegaly, and rash (moms present w/ Sx similar to mono)

Hepatitis A virus

PICORNAVIRUS- ss + sense RNA; naked icosahedral capsid Fecal-oral transmission: contaminated water/shellfish; food handlers, daycare workers, kids High risk groups/conditions: unsanitary conditions, overcrowded conditions Capsid is even more stable than other picornaviruses to acid and other treatments (resistant to detergents, acid (pH of 1), and temperatures as high as 60°C, and it can survive for many months in fresh water and salt water); only one serotype of HAV Replication: replicates like other picornaviruses- interacts specifically with a receptor expressed on liver cells and a few other cell types. Unlike other picornaviruses, however, HAV is not cytolytic and is released by exocytosis. Ingested and enters the bloodstream through the oropharynx or the epithelial lining of the intestines to reach the parenchymal cells of the liver. The virus replicates in Kupffer's cells and hepatocytes. It is released into the bile and from there into the stool, where it is heavily shed ~10 days before symptoms of jaundice appear or antibody can be detected (asymptomatic shedding). Symptoms stem from immune-mediated damage to the liver. The symptoms occur abruptly 15-50 days after exposure- fever, fatigue, nausea, loss of appetite, and abdominal pain --> Icterus (jaundice), results from damage to the liver, occurs when cell-mediated immune responses and antibody to the virus can be detected. Symptoms wane upon development of jaundice. Complete recovery occurs 99% of the time. Fulminant hepatitis occurs in 1-3 persons per 1000 and is associated with 80% mortality. Unlike HBV, immune complex-related symptoms (e.g., arthritis, rash) rarely occur. Most people infected with HAV in developing countries are children who have mild illness; in developed world, infection usually occurs later in life. Serologic tests: anti-HAV IgM measured by an ELISA or radioimmunoassay. Virus isolation: not performed; no efficient tissue culture systems Prophylaxis with immune serum globulin given before or early in the incubation period is 80-90% effective in preventing clinical illness. A killed HAV vaccine is available for all kids, and adults at high risk for infection, especially travelers to endemic regions. Antibody protection against reinfection is life-long. Inactivated by: chlorine tx of water; formalin, UV, B-propiolactone, Paracetic acid

HSV-1 & HSV-2

Primary oral herpes- HSV-1 (2 in young adults) Recurrent oral herpes- usually HSV-2 (generally activated from trigeminal ganglia) Primary & recurrent genital herpes- HSV-2; recurrent usually shorter in duration & less severe; in 50% preceded by prodrome of burning/tingling in area; asymptomatic shedding Encephalitis- HSV-1- results in destruction of one of the temporal lobes; characterized by erythrocytes in CSF, seizures, focal neuro abnormalities Assoc w/ HSV-1 & HSV-2: Herpes pharyngitis, herpetic keratitis (leads to permanent blindness), herpetic whitlow (finger), eczema herpeticum (in kids w/ active eczema), genital herpes, herpes encephalitis, HSV meningitis (complication of HSV-2 genital infection) HSV infection in neonate often fatal- most often contracted in birth canal. Baby is septic w/ vesicular lesions- disseminates to organs and CNS

HHV-6

ROSEOLA (Exanthem subitum)- rapid onset of high fever of a few days duration --> generalized rash that lasts 24-48 hours; dz effectively controlled and resolved by cell-mediated immunity, but virus establishes lifelong infxn of T cells

Retrovirus replication

RT uses tRNA as template to synthesize - strand DNA --> Ribonuclease activity degrades RNA genome --> + strand cDNA synthesized (DNA synthesized from RNA= PROVIRUS) --> sequences from each end duplicated, attaching LTRs to both ends --> cDNA enters nucleus --> spliced into host chromosome by Integrase --> LATE PHASE In late phase, integrated viral DNA transcribed as a host gene by HOST RNA Pol II

Metapneumovirus

Recently recognized member of the pneumovirus family (part of paramyxoviruses). Ubiquitous; almost all children have experienced it and are seropositive. Infections by human metapneumovirus, like its close cousin, RSV, may be asymptomatic, cause common cold-like disease or serious bronchiolitis and pneumonia. Seronegative children, elderly persons and immunocompromised people are at risk to disease. It probably causes 15% of common colds in children, especially those of which are complicated by otitis media. Signs of disease usually include cough, sore throat, runny nose, and high fever. ~10% of patients with metapneumovirus will experience wheezing, dyspnea, pneumonia, bronchitis, or bronchiolitis. Supportive care is the only therapy available for these infections.

Rotavirus

Reoviridae; ds RNA; double capsid Transmission: fecal-oral route Cytolytic and toxin-like action on intestinal epithelium causes loss of electrolytes and prevents readsorption of water. Disease can be significant in kids<2 years old, but asymptomatic in adults. Maximal shedding occurs 2-5 days after the start of diarrhea but can occur without Sx. Virus survives well on fomites and on hands (b/c it can withstand drying). Outbreaks occur in daycares, preschools, and among hospitalized infants. Young kids are most likely to acquire a rotavirus disease. Studies suggest repeated rotavirus infections in genetically susceptible kids may increase risk for celiac disease. Rotashield- live vaccine that was removed from the US market in 1999 b/c of risk of intusseption (intestinal obstruction)

Seroconversion, Anamnestic response

Seroconversion- prior to it, blood test is negative for Ab; after it, blood test + for Ab Anamnestic response- secondary/booster antibody response to a recurrence of the infection that happens later in life (rapid production of an antibody on subsequent encounter with the same antigen). Antibody titers remain high in pts who suffer frequent recurrence of a disease (e.g. herpesvirus) IgM- recent infection IgG- old infection

Branched Chain DNA Assays

Similar to ELISA, but for amplification & detection of DNA -Uses immobilized DNA sequences complementary to relevant viral genomic sequence to capture the viral genome --> another complementary sequence binds that's coupled to a detection system Results in an extensively branched chain of DNA, in which each branch elicits a reaction that amplifies the signal to detectable levels

Papillomavirus

double stranded CIRCULAR DNA; 7-8 early genes (E1-E8) and 2 late genes (L1, L2) *All genes located on 1 strand (+ strand) capable of causing lytic, chronic, latent, and transforming infections, depending on host cell. Small coding capacity- don't encode all enzymes required for replication. However, their early genes' proteins (E6 and E7) induce an UNSCHEDULED S PHASE in non-dividing host cells, in which replicative host enzymes are expressed and used by the virus for DNA replication. E6- binds p53 and targets it for destruction E7- binds and inactivates p105RB *E6 & E7= oncogenes HPV 6&11- benign; condyloma acuminatum HPV 16&18- causes cervical intraepithelial neoplasia; cancer; at least 85% of cervical carcinomas contain integrated HPV DNA. Breaking the circular genome in E1&E2 gene regions to promote integration often inactivates these genes, preventing viral replication. However, this doesn't prevent expression expression of other HPV genes, including E6 & E7. *Koilocytes- characteristic of papillomavirus infection- enlarged keratinocytes w/ clear haloes around shrunken nuclei

Polyomavirus

double stranded CIRCULAR DNA; naked icosahedral capsid; early genes on 1 strand, late genes on other strand, noncoding region contains origin of DNA replication and transcriptional control sequences for both early and late genes Virus infections widespread, but only cause disease in immunosuppressed BK virus- renal disease in immunosuppressed. virus thought to be spread via respiratory --> disseminates to the kidneys and urinary tract where it persists for the life of the individual. It is thought that up to 80% of the population contains a latent form of this virus, which remains latent until the body undergoes some form of immunosuppression. Typically, this is in the setting of kidney transplantation- can cause renal dysfunction and loss of a transplanted kidney. Virus affects tubular epithelial cells- have viral intranuclear inclusion bodies (DECOY CELLS)- become necrotis. Decoy cells can be detected from urine cytology/allograft biopsy; viral DNA can also be detected in urine and plasma by PCR JC virus- progressivce mutifocal leukoencephalopathy (PML) in immunosuppressed. Virus establishes persistent & latent infection in organisms such as kidneys and lungs --> in immunocompromised, virus reactivated --> spreads to brain and causes PML. In PML, virus partially transforms astrocytes and kiss oligodendrocytes, causing lesions and sites of demyelination. Pts may have multiple neuro Sx unattributable to a single lesion- speech, vision, coordination, mentation, or a combination of Fxs is impaired --> paralysis of arms and legs --> death. Most pts die w/in 2 years of diagnosis

Retroviruses- General features

enveloped RNA viruses; capsid contains 2 copies of + strand RNA genome (two tRNAs base-paired to the genome within the protein core) Virion contains RNA-dependent DNA Polymerase (AKA RT) & Integrase *Reverse transcriptase- an RNA-dependent DNA polymerase that makes DNA from the RNA that is in the virion *Integrase - integrates the DNA made by RTase into the host cell genome (integration requires cell growth) Replication proceeds through DNA Intermediate (Provirus)-->provirus integrates randomly into host genome & becomes a cellular gene Subfamilies: Oncovirinae (assoc w/ cancer & neuro d/os), Lentivirinae (slow onset of dz; cause immunosuppression & neuro d/os; HIV-1&2), Spumavirinae (don't cause disease, but vacuolated foamy cytopathology) Exogenous retroviruses- actively replicating retroviruses that are transmitted horizontally- person to person. Endogenous retroviruses- retrovirus sequences that are integrated into the human genome; generally lack the ability to replicate because of deletions or the insertion of termination codons or because they are poorly transcribed Retrovirus genome has a 5'-cap and is polyadenylated at the 3'-end. At each end of the genome are long-terminal repeat (LTR) sequences. The LTR sequences contain promoters, enhancers, and other gene sequences used for binding different cellular transcription factors

HIV Envelope Proteins

gp 120- attachment protein- binds to the CD4 molecule expressed on cells of the macrophage lineage (macrophage, dendritic cells, microglial cells), as well as a second receptor, a 7-transmembrane G-protein coupled chemokine receptor (CCR5- co-receptor on macrophages gp 41- fusion protein- promotes cell-cell fusion (formation of syncitial/multinucleated giant cells)

Interferons

interfere w/ translation of viral mRNA; enhance degradation of viral & cellular mRNA, block ribosomal assembly to prevent protein synthesis & viral replication. Interferon targets Hep A, B, C, and papillomavirus

Orthomyxoviruses

large, enveloped, segmented ss - sense RNA (8 unique RNA nucleocapsid segments) *Genome transcribed and replicated in nucleus (unique for an RNA virus) Types A, B, and C (Influenza A affects many vertebrate species, inc. humans & other mammals and birds; B and C only in humans) Transmission: inhalation of aerosolized respiratory droplets Envelope contains 2 spike proteins: -Hemagglutinin- viral attachment protein; binds sialic acid receptors on RBCs (causing heme agglutiniation) and sialic acid receptors on upper respiratory epithelial cells. HA is a precursor molecule that requires protease activation into two separate glycoprotein subunits held together by disulfide bonds. Without this activation, the fusion of viral envelope-host cell membrane does not occur and the virus is noninfectious. Tissue expression of the responsible cellular proteases impacts viral tropism and pathogenicity. -Neuraminidase-cleaves neuraminic acid (in mucous) and disrupts mucin barrier, exposing sialic acid binding sites beneath; also cleaves sialic acid receptors to prevent clumping & facilitate release of virus from infected cells (RBCs agglutinated with influenza virus will dissociate spontaneously at 37 °C because of the activation of the NA on the viral envelope. Adding fresh virus to the same dissociated RBCs results in no agglutination because the NA destroyed the receptors for HA. The virus is still capable of agglutinating fresh RBCs with intact sialic acid-containing receptors. The cleavage of sialic acid permits the release of virus from cells. Protection against re-infection by the same strain of virus is primarily associated with the development of antibodies to HA. Antibodies to NA do not prevent infection but they do slow the spread of infection. Viruses with defective NA produce less infectious virus probably due to viral aggregate formation Influenza C lacks NA

Poxviruses

linear ds DNA virus; enveloped **DNA replication takes place in CYTOPLASM (in contrast to all other DNA viruses, which replicate in nucleus) not common in the US; cause generalized infxns w/ multi-organ manifestations, but predilection for skin Smallpox- caused by VARIOLA virus; replicates in upper respiratory tract after being inhaled --> dissemination via lympatic and cell-associated viremic spread. Internal and dermal tissues inoculated after a 2nd, more intense viremia- causing eruption of 'pocks' Smallpox=1st major human dz eradicated by vaccine (Jenner) + isolation; important bioterrorism agent Molluscum contagiosum virus- causes molluscum contagiosum- pearl like nodules; spread through direct contact w/ lesions; don't spread extensively

Adenovirus

linear, ds DNA; naked icosahedral capsid- resistant to inactivation by GI tract and drying encodes its own DNA Polymerase; synthesis of viral DNA Pol activates switch from early to late genes Transmission: respiratory droplets; fecal-oral route, fingers spread virus to eyes, mouth; fomites, INADEQUATELY CHLORINATED POOLS Virus infects mucoepithelial cells in resp tract, GI tract, and conjunctiva or cornea, causing cell damage directly Diseases: Respiratory disease (mostly common cold, but others in infants/kids/military recruits), Gastroenteritis (serotypes 40 & 41), epidermic keratoconjunctivitis, acute hemorrhagic cystitis, hepatitis, meningoencephalitis (other than resp & GI dzs, others mainly in immunocompromised/children) 3 mechanisms adenoviruses use to avoid/alter immune defense mechanisms: -encode small virus-associated RNAs that prevent activation of interferon-induced protein kinase inhibition of viral protein synthesis -viral E3 and E1A proteins block apoptosis induced by cellular responses to virus or by T cell or cytokine action -Inhibit CD8 cytotoxic T cell action by preventing proper expression of MHC I molecules Live vaccine for serotypes 4 &7 available for military use *Some adenoviruses have introns; introns were first discovered in adenoviruses *HIV vaccine study used adenovirus-5- stopped b/c some pts who were seropositive for adenovirus-5 had greater incidence of HIV infection compared to controls

Hendra & Niaph viruses

new paramyxoviruses; (ss - sense RNA virus); enveloped zoonotic; Hendra and Niaph viruses have broad host ranges, including pigs, man, dogs, horses, cats, and other mammals. Identified in 1998 after an outbreak of severe encephalitis in Malaysia and Singapore. The reservoir for the Nipah virus is a FRUIT BAT. The virus can be obtained from fruit contaminated by infected bats or amplified in pigs and then spread to humans. The human host is accidental but outcome of infection is severe - can cause flulike symptoms, sz and coma *The fruit drops from Mangrove trees into pig-farming cages directly below. How might this emerging disease be stopped at very low cost? (put a roof over pig cages)

Protease inhibitors

o Saquinavir o Ritonavir o Indinavir o Nalfinavir o Amprenavir *'NAVIRs' are protease inhibitors Slip into hydrophobic site of HIV protease and inhibit its action; Drug resistant strains arise through mutation of Protease

Reovirus

segmented, double-stranded RNA; naked, DOUBLE LAYERED CAPSID (outer and inner protein shell); virion resistant to environmental & GI conditions (detergents, acid, drying, etc). Inner capsid contains complete transcriptions system, inc. RNA-dependent RNA Pol & enzymes for 5' capping and polyA addition. (Respiratory, enteric, orphan)- no longer orphan viruses (viruses w/out disease) Includes: -Orthoreovirus- don't cause significant dz in humans; have been linked to common cold, mild URI, GI dz, biliary artresia -ROTAVIRUS- causes 50% diarrhea in kids requiring hospitalization -Orbiviruses- only cause dz in animals -COLTIVIRUSES- COLORADO TICK FEVER *Orbiviruses and Coltiviruses transmitted by arthropods; orthoreoviruses and rotaviruses NOT transmitted by arthropods *Orthoreoviruses and rotaviruses ACTIVATED IN GI TRACT by mild proteolysis to intermediate/infectious subviral particles (ISVPs), increasing their infectivity

SV40

simian polyomavirus. Early batches of polio vaccine were contaminated w/ SV40- undetected in primary monkey cell cultures used to prepare vaccine. Many people were vaccinated w/ the SV40 containing vaccines, but no SV40-related tumors have been reported

Antisense oligonucleotides

single strands of RNA or DNA that are complementary to a chosen sequence. They prevent protein translation of certain mRNA strands by binding to them. Interfere w/ translation & processing of viral mRNA. *Used to treat papillomaviruses

Prions

small proteinaceous infectious particles without detectable nucleic acid (viruses by definition contain protein and a single kind nucleic acid) Consists of aggregates of a protease-resistant, hydrophobic glycoprotein, called PrPSc (scrapie-like prion protein). Humans and other animals encode a protein PrPC (cellular prion protein) of unknown function. PrPC is closely related or can be identical to PrPSc in protein sequence but differs in tertiary structure due to differences in the folding. PrPSc is protease resistant, aggregates into amyloid rods (fibrils), is found in cytoplasmic vesicles in the cell, and is secreted. The normal PrPC, on the other hand, is protease sensitive and appears on the cell surface. A theory is that PrPSc binds to the normal PrPC on the cell surface, causing it to refold and acquire the structure of PrPSc. The PrPSc is released from the cell and aggregates as amyloid-like plaques in the brain. The cell replenishes the PrPC, and the cycle continues. Prion disease may be distinguished from classical viral encephalitis by the SPONGIFORM (vacuolated) appearance of neurons, amyloid-like plaques, and gliosis. Prions exhibit no cytopathologic effect, long incubation periods, NO IMMUNE RESPONSE, NO INTERFERON PRODUCTION, and NO INFLAMMATORY RESPONSE (maybe b/c plaques consist of host protein) Spongiform encephalopathy= vacuolation of the neurons, the formation of amyloid-containing plaques and fibrils, a proliferation and hypertrophy of astrocytes, and the fusion of neurons and adjacent glial cells are observed. Prion diseases are always slow to present in fulminating form or stage (kuru/CJD may take 30 yrs). Transmission of slow viruses is via infected tissue, or syndrome may be inherited. Infection occurs through cuts in skin, transplantation of contaminated tissues (e.g., cornea), use of contaminated medical devices (e.g., brain electrodes), and by ingestion of infected tissue. Prions not disinfected by formaldehyde, proteases, heat, or ionizing & UV radiation. Autoclaving at 15 psi for 1 hour instead of 20 minutes or treatment with 5% hypochlorite solution or 1.0 M sodium hydroxide can be used for decontamination. No tx for kuru (New Guinea)/CJD

Parvovirus

smallest DNA virus (18-26 nm); SINGLE STRANDED DNA; + and - strands (packaged separately into virions); naked icosahedral capsid Require growing cells (B19) or helper virus (dependovirus) for replication Ends of genome have inverted repeats that hybridize to form HAIRPIN LOOPS- primer for DNA synthesis small size -->limited genetic repertoire --> more dependent than any other DNA virus on host cell B19 Parvovirus- until recently, only known parvovirus- replicates in mitotically active cells; prefers those of erythroid lineage/erythroid precursors (bone marrow) -spreads via respiratory & oral secretions -Infects mitotically active erythroid precursor cells (bone marrow)--> lytic infection -Biphasic dz: Initial phase related to viremia w/ flu-like Sx & viral shedding. Later phase related to immune response, w/ circulating immune complexes of Ab and virions that don't fix complement- erythematous maculopapular rash, arthralgias, arthritis *Depletion of erythroid precursor cells and destabilization of RBCs initiates APLASTIC CRISIS in people w/ chronic anemia Dz caused by B19 aka 5th dz (5th childhood exanthema); SLAPPED CHEEK SYNDROME; ERYTHEMA INFECTIOSUM