Micro 7
Hepatitis C Virus
("non-A, non-B Hepatitis", "post-transfusion") • Flavivirus (Hepaciviridae), • An enveloped,"+"strand RNA virus. • Remains in endoplasmic reticulum, and can remain cell associated. • Inhibitsapoptosisandinterferonaction,which helps it to efficiently establish chronic, persistent infections. • Transmitted primarily in infected blood and blood products (by blood transfusions or organ donation before screening was initiated), and by sexual transmission.
Clinical manifestation flu
SX: Fever,Myalgia,Chills,Headache,Weakness, Fatigue, Sore throat, non-productive cough Young children: resembles other severe URI May present with bronchiolitis, croup (subglottic stenosis), otitis media, vomiting and abdominal pain Complications: Bacterial pneumonia, myositis, death in the elderly and immune compromised.
Diagram the structure and replication cycle of adenoviruses.
A den of lions Structure Two genera: Aviadenovirus (avian) and Mastadenovirus (mammalian). Genome is double stranded linear DNA approximately 30-40 kb long. The genome is associated with both 5' terminal protein and additional DNA binding protein. Capsid is an icosahedron (60-90 nM) containing a fiber protein (attachment protein) at each of the 12 vertices. The virion is non-enveloped.
Explain the mechanism of action of acyclovir and ganciclovir.
ACYCLOVIR (acycloguanosine) Viral enzyme thymidine kinase (TK) phosphorylates acyclovir (host TK can't) Monophosphorylated form is further phosphorylated by host cell's enzymes Phosphorylated form is incorporated into DNA It blocks elongation & viral replication GANCICLOVIR Viral protein phosphorylates ganciclovir to a triphosphate analogue (dGTP) This inhibits viral DNA pol, terminates viral DNA replication
Understand theory behind Anti-Retroviral Therapy (ART), and how it may cause Immune Reconstitution Syndrome.
ART: Using multiple drugs (3-4) in combination to lower the risk of resistance. Immune Reconstitution Syndrome Reported in chronically infected HIV-AIDS patients treated with new combinations of antiretroviral therapy (ART). Immune system begins to recover. As the CD4 count and functionality return, the immune system responds to pre- existing infections with a massive inflammatory response that makes the symptoms worse. Lecture 28: Virology VIII
Understand & explain acquired, hereditary, & spontaneous mechanisms of human prion disease development.
Acquired -Acquisition of aberrant PrPsc from contaminated food, contaminated medical equipment, transplantation w/ contaminated organ (cornea) -Absorption from gut at Peyer's Patches -Phagocytosis by lymphoid cells, followed by targeting lymph nodes & other lymphoid tissue such as tonsils and spleen -replication in lymphoid tissue, where PrPc is expressed, and converted to PrPsc -entry into CNS via nerves that innervate lymphoid tissue, followed by neuropathology Hereditary -individuals with familial forms invariably have mutations in the cellular PrP gene -PRNP gene encodes the PrPsc protein -the mutations in the PrPc gene in familial disease cause the protein to convert to PrPsc @ higher frequency→ frequent & early development of Dx Spontaneous -PrPc can spontaneously convert to PrPsc, but this happens w/ low frequency -Alternatively, could be a somatic mutation in the PrPc gene -After conversion, altered protein will promote refolding of additional PrPc → disease -KURU may have been caused by cannibalism of a sporadic CJD individual
4) Key steps in viral life cycle
Attachment: Interaction between Viral Attachment Protein (VAP) and cell surface receptor. VAP can be a capsid protein (Non-enveloped virus) or an envelope protein. Cell surface protein are usually either Glycoproteins or glycolipids. This interaction is a MAJOR DETERMINANT of HOST-RANGE/TROPISM. Penetration: Usually via Receptor mediated endocytosis (RME) or Direct entry at cell surface (DECS). In RME, the virus binds at a specific region "coated pits" which then "pinch off" to form a coated vesicle. This vesicle can fuse with other vesicle to form the endosome. Acidification induce a change in the structure of the viral protein which then mediate the release of the virion/viral genome into the cell (Fusion protein for enveloped virus and channel protein or lysis for non-enveloped viruses). IN DECS, entry by either Membrane fusion (enveloped virus) or pore/channel formation (N-E viruses) PIC 491 & 492 Uncoating and Targeting: genome can be partially or completely released from capsid during or after entry. Some DNA viruses need to be targeted to the nucleus for replication and Transcription. Replication/Gene Expression strategies: Depend on the type of genome DNA viruses: Usually 2 stages—> Early and Late gene expression Early: Expression of early genes using viral and/or cellular enzymes. TS and TL of early genes to produce early proteins which are usually regulatory proteins such as transcription factors. These proteins help with viral DNA replication. Late: After DNA replication, TS and TL of late genes to encode structural proteins (capsids...) in order to assemble the viral particle. SOME VARIATIONS: Parvoviruses—> ssDNA and therefore, need to be converted into dsDNA before TS Poxviruses—> replication in the cytoplasm and therefore must encode all proteins necessary for their own gene expression and replication. RNA viruses: Most replicate in the Cytoplasm (NOT orthomyxoviruses and retroviruses). Make sense they are already RNA so they do not need host TS machinery which is in the nucleus. Have RNA REPLICASES since they need RNA polymerase to replicate their viral RNA and the host cell cytoplasm does not have RNA dependent RNA polymerases (RDRPs). RDRPs have no proofreading and therefore, they have high mutation rates due to high error rate of RDRPs. strand RNA: Infection RNA that can be directly used for TL of viral proteins (replicases..). The replicase will synthesize the - strand that will be used as a template for making additional + strand RNA. Newly synthesized + strand can be used to produce more viral proteins, - strands or be packaged into visions. strand RNA: Have the replicase present in the infectious virion (b/c can't use the RNA to encode the replicates and replicates are not present in the cytoplasm of host). Same principle as + strand RNA: - strand converted to + strand RNA by replicase (present in virion) —> + strand RNA used to encode additional viral proteins (including replicases), and as a template for more - strand RNA. - strand RNA can be used for additional + strand (repeat of cycle) or packaged in virion. RETROVIRUSES: Have a + strand RNA that is converted to DNA by reverse transcriptase (packaged in the virion). This forms a DNA/RNA hybrid. The RNA in the hybrid is digested and replaced by DNA (using RT) giving rise to a dsDNA. Assembly and release Newly synthesized viral genomes are ENCAPSIDATED by viral proteins inside the cell and undergo a maturation step required for infectivity (in many viruses). It can involve proteolysis. N-E viruses—> virions accumulate inside the cell and are released by cell death/lysis E viruses—> envelop acquired by budding off cellular membranes. They do not necessarily kill the host cell
List the general properties of orthomyxoviridae, and their medical impact on human populations - Influenza Viruses A, B and C
Family contains three members: Influenza A,B, and C A mutation rates A>B>C Strains of influenza are classified by type (A, B, C), place of original isolate, date of original isolate, and HA/NA antigen Example: A/Bangkok/1/79 (H3N2). H1N1 and H3N2 are currently circulating in the human pop Enveloped virions, (-) strand RNA genomes Contains two glycoproteins: Hemagglutinin (HA) and Neuraminidase (NA), and membrane channel protein (M2) The virion contains 8 different segments of RNA (a segmented genome) associated with a nucleoprotein (NP), plus the viral RNA dependent RNA polymerase. Each genome segment encodes 1-2 polypeptides. Influenza A and B are the ???
•Identify which of the hepatitis viruses cause chronic human disease, and how they accomplish this.
Hep B
Compare and contrast prions and viruses.
Infectivity ↳prion infectivity SENSITIVE to Tx that destroys proteins (SDS detergent, Proteases, Phenol) UV resistance ↳prion infectivity RESISTANT to Tx targeting nucleic acids (UV/Ionizing radiation, DNAase, RNAase); viruses are NOT Resistance to formaldehyde ↳ prions resistant while viruses are NOT (still present in cadavers!) Size ↳prions are smaller than viruses; can only be seen under EM in clusters Immune responses ↳prions are cellular proteins - might explain lack of immune response; viruses elicit immune responses
Discuss the pathologic characteristics of transmissible spongiform encephalopathy (TSE).
Large vacuoles in post-mortem brain (symmetrical vacuolation) Muscle wasting
Understand mechanisms of action, benefits and limitations of influenza specific anti-viral medications.
Look at 6F above
Know the formulations for influenza virus vaccines.
Northern Hemisphere Trivalent Flu Vaccine contains: A/Michigan/45/2015 (H1N1) -pandemic like virus A/Hong Kong/4801/2014 (H3N2) -like virus B/Brisbane/60/2008-like Quadrivalent vaccines (add B/Phuket/3073/2013-like) seniors/ at risk individuals can utilize high dose vaccines Same viruses, but formaldehyde inactivated and chemically disrupted, then concentrated for HA, 4x "strength" of typical vaccine. Lecture 27: Virology VII
Describe methods for the detection of papilloma virus infections.
Pap smear Nuclear acid hybridization PCR methods
Diagram the structure and replication cycle of papilloma viruses.
Pilloma bugs Structure: Small, non-enveloped, isosahedral viruses, dsDNA, circular DNA genome. Over 100 different serotypes of HPV and can be either cutaneous or mucosal. Some are sexually transmitted such as: → HPV 16 and 17: squamous cell carcinoma of cervix → HPV 6 and 11: benign cervical warts
DX: earlier the better flu
Rapid Influenza Diagnostic Tests (RIDTs) Influenza Antigen Testing Detect Influenza A and/or B viral nucleoprotein antigens in respiratory specimens (nasal swabs) Rapid (yes/no result in 15 minutes) Limited sensitivity (50-70%), with high false negative rate Use early for maximum utility. Viral Culture or RT-PCR based detection serve as reference standards for laboratory confirmation
•Note the role of reverse transcriptase in the Hepatitis B life cycle.
Replicates through an RNA intermediate, using a reverse transcriptase enzyme encoded by the virus. DNA RNA DNA
Understand the clinical characteristics of Rabies: pathogenesis, brain characteristics, and current treatment strategies Pathogenesis:
Rhabdovirus, enveloped, helical nucleocapsid (bullet-shaped virion), ss neg RNA Virus gets into human via bite from rabies-infected animal then virus replicates in muscle and enters the PNS → passive ascent via sensory fibers → replication in DRG. Rapid onset in spinal cord → infection of spinal cord, brainstem, cerebellum, and other brain structures → descending infection via nervous system to eye, salivary glands, skin, and other organs.
Replication polyoma viruses.
Two human polyomaviruses, BK and JC, are ubiquitous but do not usually cause disease in immunocompetent individuals. They can, however, establish latent infections in kidney and potentially other tissue. In immunocompromised hosts, the viruses can reactivate and cause severe urinary tract infections (BK) or viremia and CNS infections and progressive multifocal leukoencephalopathy, PML (JC). Describe the role of BK, JC and Merkel cell viruses in disease.
Understand the concept of Zoonoses
Viral diseases shared by animals and/or insects and humans are called zoonoses.
Replication cycle adenoviruses.
Virus enters cells by receptor mediated endocytosis → induces lysis of endosome → and the nucleocapsid them targets the nucleus. Early genes are transcribed and translated using host cell proteins. These early proteins: - activate additional viral gene expression - are required for viral DNA replication - induce host cell to enter S phase (so the virus can use the replication machinery) - block apoptosis - inhibit interferon response induced by the presence of dsRNA (esp. VA RNA) In permissive cells, viral early gene expression is followed by viral DNA replication, which uses the 5' terminal protein as a "primer". Viral DNA replication is followed by expression of the late genes, which encode the structural proteins of the virus. These structural proteins are synthesized in the cytoplasm, and are then targeted to the nucleus where assembly of new virions occurs. Virus particles accumulate to high copy number, and are released by cell lysis. Adenoviruses can also establish latent or persistent infections in some cell types.
Causes: papilloma
Warts → Benign: (feet, hands, transmitted direct and indirect contact) → Genital warts via sexual transmission Laryngeal paplliomatosis: → tumors in larynx (major cause of head and neck cancer) → transmission: vaginal birth, oro-anal, or oro-genital contact → danger of airway obstruction in children.
Diagram the structure and replication cycle of parvoviruses. Structure
bombs away Smallest DNA virsuses Non-eveloped, icosahedral capsid Genome is ssDNA Genus: Erythrovirus, Species: B19
Merkel Cell Virus (MCV)
dsDNA virus,a Polyoma Virus Common if not universal infection of older children and adults Integration of MCV genome is cause of rare but aggressive form of skin cancer 80% of Merkel cell carcinomas contain MCV genome. Increased incidence in elderly or immune compromised Lecture 24: Virology IV
• Understand poliovirus genome structure, life cycle, tissue replication and human spread patterns, pathogenesis and disease progression (asymptomatic to paralytic).
flamingo Genome structure: It is a picornavirus. The picornavirus genome contains a single large open reading frame, which is translated to give rise to one polyprotein. This protein is then cleaved to give rise to the final viral proteins (VP4, VP2, etc). Tissue Replication and life cycle: Pathogenesis and disease progression • An enterovirus. • Entry into mouth • Replication in pharynx, GI tract, local lymphatics • Hematologic spread to lymphatics and central nervous system • Viral spread along nerve fibers • Destruction of motor neurons Spread: Human fecal matter to hand, sewage or solid waste landfills. Can then spread to water supply and shellfish.
5) Define tropism and the variables it depends on
tropism: Only a particular virus with a particular VAP can bind/recognize a particular cell with a particular receptor (glycoproteins). It depends on VAP (on virus) and Cell surface receptor (glycoproteins on host cell surface).
What tumor is caused by HHV-8A?
↳Kaposi Sarcoma Lecture 25: Virology V
Describe the typical cytologic morphology of CMV infected cells.
↳The histopathology of a tissue will show cytomegalic cell containing basophilic intranuclear inclusion body, known as "Owl's eye" (image on p. 561 of course pack)
Define and understand the potential outcomes of acute vs. chronic infection.
*Answered above* Acute infection is temporary, and cleared while chronic infections are persistent, and the virus remains in some form Chronic infections can cause constant shedding of virus (HIV) or virus can be "latent," wherein sometimes, no free virus is even detectable in the infected person (HSV) Examples in diagram on p. 506 of course pack
Yellow Fever
- Can cause lytic or persistent infections in both vertebrate and invertebrate hosts. Invertebrates are usually persistently infected and produce virus. - Female mosquitoes acquire virus during feeding (blood meal) on a viremic vertebrate host. - Virus infects epithelial cells in mid-gut of mosquito, spreads to circulation, and infects salivary gland. It is then released into the saliva, and transmitted to new vertebrate host. - Virus circulates in vertebrate host, and then infects susceptible target cells. - Infection can be associated with mild systemic disease, flu-like symptoms, encephalitis, arthogenic disease, or hemorrhagic disease. Sometimes progresses to liver failure (jaundice) hence term Yellow Fever
Understand disease syndromes caused by alphaviruses and flaviviruses. Flaviviruses: Human Pathogens Dengue Fever
- Dengue Fever is also known as "break-bone fever" consisting of high fever, headache, rash, back/bone pain lasting 6-7 days. - There are 4 virus strains, and rechallenge with a second strain can cause hemorrhagic fever (DHF) and Dengue shock syndrome (DSS).
Understand the Influenza virus life cycle, and host immune responses during virus infection
1) HA protein serves as both viral attachment and fusion proteins → HA binds to sialic acid residues on cell surface glycoprotein→ entry via receptor mediated endocytosis → 2) Acidification of endocytic vesicles induces a conformational change in the HA protein that exposes hydrophobic (fusigenic) regions → viral envelope fuses w/ endosomal membrane→ release of the nucleocapsid into cytoplasm → nucleocapsid is targeted to the nucleus→ 3) RNA segments transcribed into mRNA using viral transcriptase →4) most mRNa is encoded into single protein except for segments 7 and 8 which encodes 2 proteins each → Envelope (HA and NA) and M2 proteins are inserted into cell membranes→ (5) RNA is replicated (- strand to + strand to - strand) in the nucleus → 6) Genome segments are transported to cytoplasm, where they associate with polymerase and NP proteins to form the nucleocapsid → 7) virus is released by budding
Identify the virus species included in the family Herpesviridae
3 Subfamilies of Herpesviridae- differ by genome structure & biological activities Alpha: HSV-1, HSV-2, VZV Beta: CMV, HHV-6, HHV-7 Gamma: EBV, HHV-8 Important members of Herpesviridae: Herpes Simplex Viruses, Varicella-Zoster virus, Epstein-Barr virus, Cytomegalovirus; they all share similar morphology & mode of replication
Know the major steps of the HSV life cycle
ATTACHMENT & PENETRATION BY FUSION Specific envelope glycoproteins (gB, gC, and gD for HSV-1) bind to cell surface receptors (e.g., host cell receptor = heparin sulfate) Nucleocapsid + Tegument enter the cytoplasm through either direct membrane fusion at cell surface, OR receptor-mediated endocytosis followed by membrane fusion Nucleocapsids + some tegument proteins targeted to nuclear pores, where DNA + associated proteins will enter the nucleus Linear viral genome circularized within the nucleus IMMEDIATE EARLY (IE or Alpha) gene expression/protein synthesis host cell's RNA pol. & transcription factors + a virus-encoded (beta) genes; these encode enzymes needed for viral DNA replication Viral DNA replication begins (Herpesviruses encode many enzymes needed to replicate their DNA, like DNA pol, thymidine kinase - THESE ARE GOOD TARGETS FOR ANTIVIRAL Rx) LATE (gamma) genes finally expressed; these encode viral structural proteins Capsid & Tegument proteins translated on free ribosomes, and transported into nucleus to packaged DNA into new nucleocapsids Envelope proteins translated in association w/ ER, targeted to cellular membranes Newly formed virus buds through nuclear membrane LYSIS/EXOCYTOSIS/DIRECT CELL-CELL FUSION & RELEASE Hepesviruses released from cells by cell lysis, exocytosis, and direct cell-cell fusion (results in syncytia)
•Describe and contrast the major symptoms of acute vs chronic hepatitis.
Acute Hepatitis Initial symptoms - Fatigue, low grade fever - Joint/muscle aches, anorexia - Nausea, vomiting, diarrhea 1-2 weeks later (as virus replicates in hepatocytes) - Jaundice : increase in bilirubin levels - Urine will be dark brown in color - Liver area tenderness/pain - Elevated AST(aspartate aminotransferase and ALT(alanine aminotransferase) Chronic Hepatitis • Patient may be asymptomatic • Slightly elevated liver derived enzymes • Hepatomegaly/tenderness • Risk of long term liver disease.
Understand and contrast antigenic drift and antigenic shift - Understand reassortment - Impact upon yearly strain differences and pandemics
Antigenic drift: Mutation of genomes due to errors during replication Usually due to point mutations Mainly a result of RNA polymerase errors, (lack of proofreading capability) HA and NA drifts are the most important Can occur in Influenza A, B and C, but the highest rates are in Influenza A. Results in gradual changes over time, and is a cause of yearly epidemics. Antigenic shift: Reassortment of genome segments results in a dramatic change in antigenicity Several different viruses from different sources can infect the same animal, and the same cell within an animal. I.e. Influenza A can replicate in both humans and many animal species, these different viruses can come from different animals. Genome segments can randomly assort into newly formed virions. Exchange of HA- or NA-encoding segments can give rise to an antigenically distinct human virus that the population has no immunity to These new viruses are the cause of influenza pandemics.
Understand the term Arbovirus
Arthropod Borne Viruses. Viruses that can be transmitted by insects Are NOT a family rather a collection of families Includes members of Arena, Flavi, Bunya and Togaviridae. All are enveloped, RNA viruses. These viruses replicate in the insect as well as the mammalian host.
Describe the role of papilloma viruses in tumor formation.
At least 85% of cervical carcinomas contain HPV DNA (HPV 16 or 18) integrated into the cellular genome. High incidence in those who begin early sexual activity, or have multiple partners The HPV genome is episomal (not integrated into the cellular genome) in cervical warts and pre-neoplastic lesions. The HPV genome is integrated into the genome of malignant cervical cancer cells. HPV can also cause cancers of the vagina and vulva in women, cancers of the penis in men, and cancers of the anus and back or throat in men and women.
List the main classes of anti-retroviral drugs, and know their mechanisms/targets of action.
Binding Inhibitors: MOA -- prevent gp120 from binding with CCR5 receptor (don't work for viruses that use CXCR4 to get in) Fusion Inhibitors (T20): Work by interfering with HIV-1's ability to enter into cells by blocking binding or the fusion of the viral envelope with the cell membrane. This inhibition blocks HIV's ability to enter and infect the human immune cells. Inhibits gp41. Nucleoside Analogue Reverse Transcriptase Inhibitors: NRTIs -- MOA: add nucleoside analogue into viral cDNA during reverse transcription since it lacks 3'OH group it serves as a chain terminator thus blocking the replication cycle. Ex. drug AZT Non-nucleoside reverse transcriptase inhibitors (NNRTIs): MOA -- These drugs bind to RT and block its activity so there is no incorporation of nucleotides. Integrase inhibitors - block action of viral integrase so it proviral DNA genome can't integrate into host cell genome. Protease Inhibitors: interfere with the processing of viral proteins.
Explain the role of CD4+ T cells and CD4+ T cell counts in HIV infection and conversion of HIV to AIDS.
CD4 T- cell counts < 200 /ml Viral load > 75,000 copies/ml HIV wasting syndrome (weight loss and diarrhea for> 1 month)
Replication parvoviruses
Can only productively infect mitotically active (proliferating) cells, because they are dependent on cellular enzymes, and cannot induce quiescent cells into the cell cycle. Adeno-Associated Virus (AAV) requires a "helper" virus to grow, an Adenovirus. The helper is thought to induce a cellular state conducive to viral replication.
•Understand role of the different hepatitis viruses in the induction of cirrhosis and hepatocellular carcinoma.
Chronic Hep B can lead to cirrhosis and hepatocellular carcinoma- • HBV genome (or parts thereof) are integrated into tumor cells and the cells express viral antigens. • Mechanism of transformation is unknown, but the X gene product (Hbx) is involved. Possibilities include: - continued proliferation of liver to regenerate damaged tissue - activation of cellular genes due to viral insertion, - direct action of some viral proteins to stimulate proliferation. Hep D- Causes direct cytopathic effects in liver (cirrhosis and "fulminant hepatitis"). Hep C-HCV and Hepatocellular Carcinoma • HCC risk increases with longer times after primary infection • Studies suggest increased risk of other cancers such as Non-Hodgkin's Lymphoma and Multiple Myeloma, as well as smoking and alcohol related cancers such as cancers of the pancreas, lungs, kidneys, and oropharyngeal. Can also cause cirrhosis Lecture 29: Virology IX
2) Components of virion structure
DNA vs RNA: linear or circular ds/ss DNA VS only ds/ss LINEAR RNA. RNA can be either + stranded and therefore, directly translated (TL) as the genome serve as a mRNA OR - stranded and therefore, need to be converted to + strand RNA before being used for protein synthesis. RNA viruses can also have SEGMENTED genomes (> 1 RNA molecule present in virion). Capsid structure: Either a Helix or an Icosahedron. They are composed of a structural subunit (protomers) that can be single or several proteins. Morphological units or capsomers = clustering of promoters around an axis of symmetry. They may have spike projecting from the capsid. Envelop structure: Not always present. While a lipid bilayer made of Host-cell lipids, it contains virus-virus-encoded proteins (glycoproteins). They are formed via budding through cellular Membranes (plasma Membrane, ER membrane ...). Matrix proteins underneath the envelope link it to the nucleocapsid. Virion associated proteins: Non-structural proteins such as nucleic acid binding proteins, replicates, Transcription factors, RNAs... Usually in low amount.
Replication: papilloma
Dependent on host cell polymerases to express their genes and replicate. HPV can replicate lytically in permissive cells. In some cells the virus (DNA) can persist in either integrated or unintegrated (episomal) forms. In these persistently infected cells it stimulates cell proliferation due to the expression of viral early genes.
• Know Polio vaccine recommendations.
Due to the possibility of vaccine associated disease, OPV (oral attenuated virus) has not been recommended for routine immunization in the US since 1999. All infants and children should receive four doses of IPV at 2, 4, and 6-18 months of age, and 4-6 years of age. The minimum age for dose 1 administration is 6 weeks. If accelerated protection is needed, the minimum interval between doses 1-3 is 4 weeks. The minimal interval from dose 3 to dose 4 is 6 months. The final dose should be administered at age 4 or older, regardless of the number of previous doses. Adults who are traveling to polio-endemic areas and are unvaccinated or whose vaccination status is unknown should receive IPV. Two doses of IPV should be administered at intervals of 4-8 weeks; a third dose should be administered 6-12 months after the second. WHO Recommendations for Routine Immunization in Developing Countries The immunization schedule recommended by WHO calls for OPV to be given. The original OPV was composed of three types of attenuated poliovirus (Sabin strains), but a bivalent vaccine against currently circulating strains is now in use. Inactivated polio vaccine (IPV) is sometimes being used in conjunction with the OPV.
Stages of viral infection:
Entry into body Initiation of infection @ 1° site Activation of innate protection/immunity Replication of virus @ 1° site, & possible spread through bloodstream 1° viremia) For some viruses, replication in 2° organs (liver, spleen, bone marrow, etc.) →Sx & 2° viremia Possible infection of final target tissue (brain, etc.) Host responses→ Immunopathogenesis Release/shedding of virus (skin, saliva, respiratory secretions, genital secretions, fecal/oral, blood, maternal-neonatal); can be from 1°, 2°, or 3° target tissues Resolution of infection OR persistent infection/chronic disease
Understand hemorrhagic diseases caused by Filoviruses, (Ebola and Marburg)
Filamentous, enveloped, neg strand RNA, cause severe hemorrhagic fever. Level 4 pathogens Both are primarily isolated and observed in parts of Africa Transmission: infected animal reservoir, then leads to human to human spread via contact with infected blood/secretions Replicates rapidly in monocytes, macrophages, dendritic cells → Elicits pro-inflammatory cytokine "storm" Incubation period 5-10 days Flu like initial symptoms, lead to Hemorrhagic Symptoms: Petechiae, ecchymoses, bleeding out of mucous membranes Rash, maculopapular, on trunk After 2nd week of symptoms either resolves, or multi-organ failure, and death
Rotavirus
Five species (A-E), with Group A the most common cause of childhood diarrhea and gastroenteritis (90% of cases) When ingested, survives GI environment • Infects up to 95% of children by age 3 • Responsible for 50% of hospitalizations in children with diarrhea, autumn, winter and spring • NSP4 protein has toxin-like activity (similar to Cholera toxin), prevents water absorption, causing net water secretion and loss of ions (diarrhea) that can result in severe dehyrdation. • Two vaccines (live, oral) for Rotavirus are now in use in US.
Understand the biology of Rubella Virus* (a + strand virus).
General info 3rd disease of the Six classic childhood exanthems/rash Due to rubella virus, a member of Togavirus Not part of the paramyxovirdae but is in the MMR vaccine Referred as German measles Single strand (+) sense non-segmented RNA genome that is enveloped Pathogenesis Transmission Respiratory secretions, aerosols, congenital Incubation: 13-20 days Enters and infects nasopharynx→ lungs → Spreads to lymph nodes and monocytes/macrophages → Viremia Virus can infect the placenta and spread to fetus Clinical Manifestation Children and adults: Low grade fever, rash, sore throat, lymphadenopathy, Maculopapular rash begins on face, spreads to torso and extremities ( Lasts from 12 hours to 3-4 days) Adults: more severe disease with arthritis and arthralgia Congenital infections: Hearing Loss/Deafness (Most common sequela of congenital Rubella infection); Heart Defects such as Persistent Patent Ductus Arterious; Neurological:Psychomotor retardation, Cognitive delays ,Microcephaly; Ophthalmic: Cataract, Glaucoma, Retinopathy, Micro ophthalmia; Intrauterine Growth Restriction (IUGR); Thrombocytopenic purpura - ("blueberry muffin" appearance); Hepatomegaly/Splenomegaly DX: serology Treatment/prevention: MMR Vaccine; no specific antiviral treatment
Understand the functional significance of HA, NA and M2 virus proteins
HA: Hemagglutinin: viral attachment protein, fusion protein, target of neutralizing antibody. Segment 4. Major antigenic determinant NA: Neuraminidase: cleaves sialic acid, promotes virus release. Segment 6. Major antigenic determinant M2: Integral membrane protein: forms membrane channel, facilitates uncoating, target for amantadine. Segment 7
Correlate relative CD4+ T lymphocyte count and HIV RNA levels with HIV disease progression.
HIV causes lifelong infection (persists) due to its ability to suppress and evade the host adaptive immune responses. Ways it does this include: Inactivation/killing of CD4 T cells and macrophages. Antibody coated virus can be taken up by macrophages, but instead of being killed it can replicate in macrophages. Antigenic drift of viral antigens, especially gp120, which allows the virus to evade antibody responses. Due to central role of CD4+ T cells, their loss leads to severe immune deficiency. --- Inability to control virus infection. --- Opportunistic Infections --- Tumor Development Possible "latent" infection of macrophages (macrophages become reservoir), and limited expression of viral genes, --- infected cells do not have viral antigens on surface, and are therefore not recognized by CTLs.
Know the formulation of HPV vaccines and recommendations for their use.
HPV vaccine(s) composed of recombinant viral capsid proteins that self assemble into virion like particles (VLP). 3 (2) shots over 6 mo. • Gardasil and Gardasil 9 protect against HPV 6,11,16, 18 (cervical cancer, anal cancer, cervical warts). • HPV 16,18 cause ~80% of cervical cancer • HPV 6, 11 cause 90% of genital warts • CDC Advisory Comm. On Immunization: • Females age 11-12 get the vaccine, (young as 9, old as 26) • Males age 11-12 (young as 9, old as 21) • Cervarix: protects only against strains 16,18 • Do not give to pregnant individuals, or the ill, or if allergic to a vaccine component
Discuss the major properties of herpesviruses that distinguish them from other human viruses
Herpesvirus genomes = large, dsDNA b/n 100 and 250 kb in length, complex; allow virus to evade host immune system, persist in populations -usually have terminal and/or inverted repeat sequences, & unique sequences -presence & arrangement of repeats are features that determine subfamily, can result in many different isomeric forms of same genome Herpesvirus has a protein core that looks like a spool with DNA wrapped around it They have icosahedral capsids "Tegument" matrix - this is made of 15-20 proteins, and unique to Herpesviruses Envelope made of host cell lipids & viral proteins
Understand the cause and severity of Smallpox due to Variola, and its prevention/eradication
Highly contagious, strict human disease, inhalation via airborne droplets, person to person transmission, direct contact with infected body fluids or objects. Lesions develop in mucous membranes of the nose and mouth as well on skin - Ulcerate soon after formation, releasing large amounts of virus into the mouth and throat 8-14 days after onset of symptoms - Pustules form scabs - Leave depressed depigmented scars upon healing (pox) Variola major → extensive rash, high fever, 30% fatal Variola minor → less common, 1% fatal Tx: none, only supportive care Prevention: vaccine → life recombinant virus with Vaccinia NOT Variola. Eradicated from planet in 1980. Lecture 30: Virology X
Know the host cell receptor for influenza: - Avian - Human
Human strains bind sialic acid alpha-2,6 linkages Avian strains bind sialic acid alpha-2,3 linkages
Describe the roles of humoral and cellular immunity in antiviral defenses.
Humoral Immunity - blocks initial stages of virus life cycle -due to Ab binding to molecules on outside of free circulating virus, primarily effective against EXTRACELLULAR stage of virus life cycle -neutralizing Abs are the key - they prevent the virus from entering and/or replicating in host cells by blocking: Attachment Penetration Membrane fusion Uncoating -Ab-coating→opsonization; FcRs on cell surface mediate virus binding to cell -enveloped Ab-coated viruses directly lysed by complement (pokes holes) -virus infected cells coated w/Ab are bound to viral Ags such as envelope proteins; can be lysed by complement or killed by NK cells via antibody dependent cellular cytotoxicity (ADCC) *limits: not as effective late in infection since Ab can't detect virus inside cells; Abs alone can't confer long-term immunity; cellular immunity required Cell-Mediated Immunity (T cells) -TCR recognizes viral Ag in association w/ self Class I/Class II MHC molecules -TCR recognizes processed Ags (i.e., peptides), derived fr. any viral protein -Class I MHC molecules present on surface of almost all cells; Ags in association w/ Class I MHC molecules recognized by TCR on cytolytic cells (Tc,CD8+) -When cells infected w/ virus, newly synthesized viral proteins bind to Class I MHC & are presented at cell surface; recognized & lysed by Tc cells -Tc cell activation requires 2 signals: Ag binding (Class I MHC) + Th cells -Tc killing is: Ag-specific, self-restricted, requires cell-to-cell contact -Tc cells not killed during process, can act more than 1x -Class II MHC molecules expressed mostly on Ag-presenting cells like mɸ; APCs take up viruses fr. outside, then degrade them to make peptides which bind to Class II MHC -Ags presented in association w/ Class II MHC recognized by Th (CD4+) cells -Activated Th cells produce cytokines (IL-2, IL-6, etc.) that "help" other branches of immune response; some effects of cytokines are to assist in activation of B cells, Tc cells, & NK cells
List tissue/cellular locales where HSV-1, HSV-2, VZV, EBV, CMV, or HHV-6&7 become latent Describe the clinical manifestations of HSV-l, HSV2, VZV, EBV, CMV and HHV-6 & 7.
I combined my responses to these two LOs into the single table below
Alphaviruses (Togaviridae): Human Pathogens Chikungunya virus -
Initial symptoms include high fever, headache, rash on trunk and sometimes limbs, arthralgia affecting multiple joints. Acute symptoms usually resolve within 5-7 days, but joint pain can persist for long periods (up to years). Semliki Forrest Virus Sindbis Virus Eastern and Western Equine Encephalitis Viruses
•Understand the biology of Coronaviruses and their role in respiratory disease.
Kingdom of SARS Enveloped virions;80-100nm.The envelope contains club-shaped projections (glycoproteins) that give the virion its "corona", or crown-like appearance. • Plus-strand(+)RNA genome; - 27,000-30,000 bases in length. • ThegenomicRNAisassociatedwiththeN protein to form a (loosely) helical nucleocapsid. Major Coronavirus Proteins E2 (peplomer, spike): Receptor binding, membrane fusion, major viral antigen. E1 (membrane glycoprotein): budding and envelope formation. N: Nucleoprotein, binds to RNA. L: Polymerase; RNA Dependent RNA Polymerase HI: Hemagglutinin (some viruses) •Coronaviruses are common causes of upper respiratory infection, especially in adults • They are the second most common (10-15%) cause of "colds", behind Rhinoviruses. These infections are usually quite mild and self-limiting. • Multiple strains, difficult to grow •Transmission likely via aerosols and droplets, and possibly mechanical transmission (ie via mosquito proboscis) •Coronaviruses may occasionally cause enteric infections (mostly in infants <12 months). •Coronaviruses rarely cause neurological syndromes.
Describe various methods for detection and diagnosis of viral infections
Laboratory Diagnosis: Anti-viral Ab detection using serum Virus neutralization Hemagglutination HI ELISA RIA Western Blot, etc. Viral Protein/Particle Detection in serum or tissue PCR RT/PCR in situ hybridization Northern Blot Southern Blot Cytological exam of tissue EM Fluorescent Ab Visible lesions/CPE Virus isolation Growth in tissue culture Observation of CPE (cytopathic effects) Cloning/Sequencing of Genome
Define latency, and describe how latency is maintained in HSV
Latency: a virus remainS dormant within a cell as part of a persistent infection Herpesviruses demonstrate latency in specific target cells (neurons for HSV) Viral DNA persists episomally in latently infected cells with very little viral gene expression - this means that no viral proteins are detectable; Latency Associated Transcripts (LATS) are RNAs made, but they maintain the latent state Cellular stress conditions (stress, trauma, fever, UV light) can reactivate latent herpesviruses → infectious virus
7) contrast viruses with lytic cycle and those that end with budding and release
Lytic cycle: Virion accumulate in host cell and are release by bursting the cell. (cell lysis). Budding: Virion are slowing and progressively release from the host cell gaining an envelope (host lipid bilayer) when getting out. Lecture 22: Virology II
Begin to understand and describe the mechanisms underlying viral pathogenicity.
Mechanisms of Viral Pathogenesis include: Direct cell killing Lysis Inhibition of cell DNA/RNA/protein synthesis Altered membrane structure or function Disruption of cytoskeleton Altered cell permeability, etc. Direct infection of cells within immune system → immunodeficiency Indirect effects on immune system Immunopathology Inflammation Fever Edema Vascular permeability Autoimmunity Oncogenic transformation
Hep D
More info in next question
3) Virus Classification
Morphology (size, shape, envelope...), Genome (DNA/RNA, +/- strands...), Genome organization and replication strategy, Proteins (#, size, sequence...), Antigenic properties/serological relationships Biological properties (host range, mode of transmission, pathogenicity, tissue tropism...)
List the major antiviral drugs used to treat HSV infections.
Nucleoside analogues (effective against HSV and VSV) -Acyclovir -Famciclovir (Famvir) & Valacyclovir (Valtrex) - better oral bioavailability than Acyclovir
Describe the time course, mechanisms of spread of parvovirus B19.
One of 6 "Classic Childhood Exanthems". Most often affects children between ages of 4-12 years old 7 day incubation period Primary replication in respiratory tract, followed by secondary replication in bone marrow where it infects and kills replicating erythroid precursor cells. Contagious during this period; virus is released in oral and respiratory secretions. Symptoms include fever, headache, chills, malaise, myalgia Viremia clears with appearance of antibody complexes precipitate in skin and joints, causing rash and arthralgia Rash appears on both cheeks " face slap-disease", followed 1-4 days later with erythematous maculopapular rash on trunk and limbs. No longer contagious at this point No specific therapy, no vaccine Know the typical outcome and potential complications of B19 infection. Parvovirus replicates in RBC precursors In patients with chronic hemolytic anemia (ie sickle cell, others) an aplastic crisis can occur. In the immunocompromised, can cause relapsing or persistent anemia. Infection during pregnancy: - 50% of population has immunity - In seronegative women: - When infected, virus can cross placenta - Virus replicates in fetal erythroid cells, causing fetal anemia, can be severe and cause hydrops fetalis (abnormal fluid buildup in two or more areas of a fetus or newborn).
Know the general properties of the Paramyxoviridae, and the pathophysiology of: Parainfluenza Virus, Respiratory Syncytial Virus, Measles Virus,Mumps Virus.
Paramyxoviridae (-) strand, non-segmented genome Enveloped Includes the following genuses:; Morbilivirus, Rubulavirus, Paramyxovirus, and Pneumovirus
Recognize common bacterial, viral, and fungal opportunistic infections and tumors observed in HIV positive patients.
Parasitic Toxoplasma gondii Cryptosporidium Fungal Candida albicans Cryptococcus neoformans Pneumocystis carinii Histoplasma capsulatum Viral CMV Herpes Zoster and Herpes Simplex EBV Bacterial Mycobacterium tuberculosis Mycobacterium avium-intracellular complex
Diagram the structure and replication cycle of polyoma viruses. Structure
Polyomavirus JC and BK - Et Tu, BK? Small, non-enveloped DNA viruses. Circular, double stranded genomes
Describe the hypothesized formation of amyloids by PrPsc.
PrPsc interacts w/ endogenous PrPc PrPsc induces conformational change in PrPc, becomes PrPsc Accumulation of PrPsc PrPsc proteins form amyloids (multimeric aggregates) Amyloids get internalized Amyloids accumulate over long periods of time Neurological Dx Chains of amyloids break into fragments Fragments act as seeds for conversion of PrPc→PrPsc
Discuss the role of protein folding & secondary structure in the development of prion diseases.
PrPsc promotes refolding of PrPc and this leads to development of prion diseases PrPsc has a high 𝛽-pleated sheet content (2° structure) compared to PrPc, which is high in 𝛼-helices
Explain the difference between the normal prion protein (PrPc) and abnormal prions (PrPsc).
PrPsc= "prion protein from scrapie" is the abnormal form of PrPc; while they both have same primary AA sequence, PrPsc is more resistant to protease Tx than PrPc
Outline the role of interferon in antiviral defenses.
Role of IFN-𝛼 & IFN-𝛽 in Antiviral Response: IFN-𝛼 & IFN-𝛽 = proteins of approx. 20 kDa Infected leukocytes induced to synth. IFN-𝛼 Infected fibroblasts/epithelial cells induced to synth. IFN-𝛽 dsRNA produced during viral replication cycle is a signal to induce IFN synthesis IFN binds to receptors on BOTH infected & uninfected cells Binding to IFN activates up to 100 genes→ "antiviral state" "Antiviral state" activated to interrupt viral life cycle
6) Compare and contrast how various viruses (ss/ds linear/circular RNA/DNA) initiate and sustain infections
See #4 Initiate RNA TS: some need to go into the nucleus and some don't. Initiate viral protein TL: early and late gene expression Initiate viral genome replication: some encode their own replicases, some have replicase in their virion and some use host machinery.
Consider the likelihood of acquiring a prion disease sporadically, iatrogenically or genetically.
Sporadically -incidence of sporadic CJD is about 1/1,000,000 per year (VERY RARE) -there could be a somatic mutation in the PrPc gene, but spontaneous conversion of WT PrPc to PrPsc is rare Iatrogenically - transmission after tissue transplantation (cornea, dura mater grafts, reuse of stereotactic depth probes) has occurred; increased risk with LP, handling CSF, or other tissues derived from TSE patients Genetically -15% of CJD cases are familial
Brain characteristics: Rhab
The neurologic symptoms specific to rabies next appear, last 2-10 days •Hydrophobia (fear of water), the most characteristic symptom, occurs in 20% to 50% of patients. It is triggered by the pain associated with the patient's attempts to swallow water. •Paralysis of swallowing muscles •Focal and generalized seizures, disorientation, and hallucinations. •From 15% to 60% of patients exhibit paralysis as the only manifestation of rabies. The paralysis may lead to respiratory failure. Tx: Fatal w/o tx •Steps in Treatment: Treatment of wound Immediate immunization with vaccine in combination with anti-rabies Ig until patient produces their own antibodies : - Human rabies Immunoglobulin (HRIg) - Equine antirabies serum Rabies Vaccine: given in early infection -Administered IM on day 0,3,7,14, and 28 or - Intra-dermal (lower dose , multiple sites) on day 0,3,7, 28, and 90 *We don't need to know day #s, just know that Tx is given multiple days -NM
List the host cell(s}, host cell receptor and co-receptor for HIV. Understand the clinical implications of being infected by X4 or R5 HIV viruses.
The virion attaches to the cell via an initial interaction between gp120 and CD4, followed by an interaction with a chemokine co-receptor, CCR5 or CXCR4. The receptor and co- receptors play critical roles in the cellular tropism of the virus. CD4/CCR5 - "R5 virus", initial infection → infects mϕ and DC CD4/CXCR4 - "X4 virus", later in infection → infects T cells. CD4/CXCR4&CCR5 - "X4/R5" → infects mo, DC, and T-cells. Following receptor/co-receptor binding, gp41 mediates fusion of the viral envelope with the cell membrane. After membrane fusion, the nucleocapsid is released into the cytoplasm.
Describe the time course, mechanisms of spread, and diseases caused by adenoviruses.
Time course: virion is stable to drying, detergents, and GI secretions. Mechanism of spread → aerosol, close contact, fecal-oral route. Diseases: respiratory disease, conjunctivitis, hemorrhagic cystitis, and gastroenteritis.
List the determinants of cell type/tissue tropism.
Tissue tropism is mainly due to difference in penton base and fiber proteins (protein attachments on vertices of capsid)
Understand the transmission and clinical manifestations of HIV infection.
Transmission: blood, sex, perinatal (intrauterine,peripartum, breast milk) Clinical: Primary/Acute HIV (2 weeks-3 months after exposure) Initial infection is usually due to an "R5" virus infecting CCR5 expressing cells. Symptoms include fever, fatigue, rash, headache, swollen lymph nodes, and sore throat. Some individuals may be asymptomatic Large amount of HIV in the peripheral blood Immune system begins to respond to the virus by producing anti-HIV antibodies; this is seroconversion. Antibody testing prior to this may not be positive "-window period", although newer tests are very sensitive. Clinically Dormant Stage / "Latency" Can last years (without HAART treatment) Asymptomatic Level of virus in blood decreases and stays at "steady state" Most of the virus is replicating in the lymphoid tissue. Mutation of envelope protein allows infection of CXCR4 expressing T cells. CD4+ T lymphocyte destruction eventually occurs.
Zika Virus
Transmitted during Pregnancy. During pregnancy a pregnant woman can pass Zika virus to her fetus during pregnancy. Zika causes microcephaly, a severe birth defect that is a sign of incomplete brain development. Sexual Transmission. Zika virus can be passed through sex from a person who has Zika to his or her sex partners.Possibly transmitted via Blood Transfusion. Japanese encephalitis West Nile encephalitis - Possible flulike syndrome, encephalitis. St. Louis encephalitis.
Know potential treatment/prevention strategies for adenovirus infections.
Tx: no specific antivirals for adenovirus infections, some broad spectrums could be used like Cidofovir/Brincidofovir for dsDNA virus. Vaccine for types 4 and 7 (live, oral) approved for military personnel.
Explain the difference between HIV-l and HIV-2.
Type 1 = worldwide Type 2 = only in West Africa. Less virulent than 1.
Hepatitis B (a hepadnavirus)
• "Serum Hepatitis" - 1 in 20 in US have been infected • Small, enveloped DNA virus. • Genome is 3.2 kb double stranded circular DNA with single stranded gaps. • Replicates through an RNA intermediate, using a reverse transcriptase enzyme encoded by the virus. DNA RNA DNA • Surface antigen containing particles (HBsAg) are secreted into the serum of infected patients, are immunogenic, and were the source of the first HBV vaccine. Their presence is diagnostic of active infection. • Transmitted via blood and blood products, sexual transmission, perinatal transmission. • Can cause acute or chronic, symptomatic or asymptomatic disease.
Understand the role of vaccination and antiviral drugs in preventing/treating viral diseases.
Vaccination - synthesis of neutralizing Ab to block early stages of viral life cycle herd immunity: 85-95% of population must be immunized to break the cycle of infection/spread to eliminate specific viral diseases Attenuated Live & Inactivated Viral Vaccines Attenuated Live: selected by growth in cell culture ∴ have lost some pathogenicity; stimulate BOTH humoral & cellular immunity; confer long-term immunity *CAN: cause Dx. esp. in immunocompromised; "revert" to virulence (loophole is use of molecular biology to introduce deletions into virulence genes) Inactivated: virus inactivated by chemical/physical procedures to eliminate infectivity without compromising antigenicity; requires both adjuvants & multiple doses *INEFFICIENT @: inducing cellular immune response & long-term immunity Subunit Vaccines - using viral protein as immunogen to induce neutralizing or protective Abs w/ *same dis/advantages as inactivated vaccines above Recombinant Viral Vaccines - live virus expressing gene for a protein w/ *similar dis/advantages as attenuated live virus vaccine above, but w/less danger of reversion/Dx DNA Based Vaccines - DNA encoding specific viral proteins injected IM to confer long-term immunity via cellular immune response; *cheap & safe Antiviral Rx - goal of that inhibits viral replication w/o harming host; can target any stage of viral life cycle (fr. attachment → release/maturation)
Understand the HIV life cycle.
Viral RNA → DNA via RT → RNA/DNA hybrid RNA strand in the hybrid is digested by RNaseH of the RT Second DNA strand is made using the new DNA strand from hybrid as template. Now you have dsDNA = "proviral DNA" Long-Terminal-Repeats (LTR) is formed at each end of genome. Proviral DNA enters the nucleus and integrates into host cell's DNA at random sites using viral integrase. Now, the proviral DNA is replicated each time the host cell divides. The integrated proviral DNA is TS and TL to make viral RNAs and proteins. The viral promoter and polyadenylation signals are located in LTR. The viral RNAs produced can be either used to make protein or as new genome. Newly made viral RNAs are packaged into nucelocapsids in the cytoplasm and bud through the plasma membrane to make an envelope. Now they can infect another cell.
Outline the replication strategy of minus strand viruses.
Viral genome cannot serve as mRNA Strategy Virion contains replicase (RDRP) protein Replicase must be used to synthesize a (+) strand RNA in cytoplasm of infected cells except for orthomyxovirus Viral protein synthesis can begin
Describe the structure of HIV.
Viral genome is plus "+"sense, but is not used directly as mRNA. Each virion contains 2 identical copies of viral mRNA that are joined together near their 5' ends. Viral genome is encapsidated by the capsid protein p24 (CA). Envelope contains both transmembrane (TM, gp41) and surface (SU, gp120) proteins. Underlying the envelope is a matrix protein (MA, p17). Virion also contains nonstructural proteins including the reverse transcriptase (RT, or POL).
Define the general characteristics of viral infection cycles.
Viral infections are cell-type and/or species-specific (i.e., HIV doesn't affect dogs) Type of cells infected represent the host range and/or tissue tropism of the virus Cell/Tissue specificity determined by cellular receptors, enzymes, etc. If a virus can replicate & produce progeny in a cell, that cell is known as PERMISSIVE; if not, NON-PERMISSIVE Infection can be abortive/failed if in non-permissive cells or if attenuated viruses Successful infection of cells can be LYTIC/NON-LYTIC; lytic → cell death Sometimes, non-lytically infected cells continually produce virus (via budding); virus could also be "dormant" in the cell, and may/may not be activated in future (BOTH examples of persistently infected cells) Infection can either be temporary (acute infection, cleared) OR persistent (chronic infection, virus remains in some form) Persistent infections can cause constant shedding of virus (HIV) or virus can be "latent," wherein sometimes, no free virus is even detectable in infected person (HSV)
Describe the pathways of entry and stages of viral infection in humans.
Viral infections can enter via: Respiratory Tract Digestive Tract Urogenital Tract Lesions (scratches, abrasions in skin) Conjunctiva (eye) Direct blood contact Vertebrate bites Arthropod bites (mosquitos, ticks, etc.)
Explain what is meant by the "viral set point" and "window period" in HIV infections.
Viral set point: Reflects a stabilized HIV virus load in a person (ie, particles /ml, or genomes /ml of blood) after the acute phase of infection has ended. Higher Viral Set Point-faster progression to AIDS Lower Viral Set Point-slower progression to AIDS Window period = test for Antibodies too early before the immune system kicks in so you get a false negative if the person is truly infected.
• Understand Coxsackie Virus groupings relative to their disease characteristics.
caged david • Primarily seen in summer months in infants and young children • Transmitted via fecal-oral route. • Herpangina, can be caused by several group A viruses. •herp, an itching, and angina, a sore throat, literally "a choking", due to vesicular-ulcerated lesions on pharynx, palate, uvula and tonsils. •These infections cause fever, sore throat painful swallowing, anorexia and vomiting. •Hand, Foot and Mouth Disease: commonly caused by Coxsackie virus A16. •Vesicular lesions on hands, feet, mouth and tongue. Coxsackievirus B: Manifestations •Can cause fever, sore throat, rashes, but additionally: •Myocarditis •Fever with sudden, unexplained heart failure •Occurs sporadically in older children and adults, but is most threatening to infants •Pleurodynia (Bornholm Disease, the Devils grip) •Fever and unilateral low thoracic pleuritic chest pain. •Coxsackievirus (Aseptic) Meningitis: •Fever with headache and meningeal signs •Can also be caused by an echovirus
• Understand the structure and life cycles of Norovirus and Rotavirus.
ship Norovirus :• Small, round gastroenteritis viruses. • Plus"+"strand RNA viruses,non-enveloped. • Spread by oral/fecal route; infected people can shed virus for up to 2 weeks after symptoms cease. • Resistant to heat, pH,detergent. • Lasts 1-3 days,self-limiting,rehydration therapy as needed. little boats Rotavirus: • ds RNA genome, with 11 RNA segments • Non-enveloped, double layer capsids. • When ingested, survives GI environment
Major characteristics of viruses
size: very small life cycle: Obligate, intracellular parasites parasitic attributes: They lack metabolism and therefore, are dependent on the host cells Replication: binary fission
•Understand members of the Picornaviridae and their global impact on human health.
zoo • Plus strand RNA viruses, non-enveloped • 9 genera • Important Human Pathogens include: - Enterovirus • Poliovirus- almost eradicated but wild and cVDPV cases still happen • Coxsackievirus (A and B) • Echovirus • Enterovirus D68? (emerging disease, Polio like) - Rhinovirus • Cause at least half of upper respiratory tract infections "common cold". - Hepatovirus • Hepatitis A virus
•Distinguish the major properties of Hepatitis A, B,C,D and E viruses. Hep A-
• Also known as infectious hepatitis. • Is a member of the picornavirus family. Naked icosahedral capsid that is very stable to acid and other treatments. (+) strand RNA genome (7470 nt). Infects via receptor found on liver cells and some other cell types. Not cytolytic, is released by exocytosis. Most children asymptomatic, adults demonstrate more symptoms Rarely fatal and does not cause chronic disease. Prevalent in less developed countries Fecal oral Enters through oropharynx or intestine then targets liver • Virus is produced in liver, then released into bile and stool. No apparent cytopathic effects of infection. • Tc (cytotoxic T) cells lyse infected cells, enhanced by ADCC. • Liver pathology is likely due to the host immune response.
•Discuss the clinical implications of co-infection with HBV and HDV
• Can only infect cells infected with HBV; uses HBsAg as it's coat protein and attachment protein to infect cells. So, immunization for HBV would also protect against HDV infection. • Circular genome is surrounded by delta antigen. • People can either be co-infected with HBV and HDV, or people with HBV can be "superinfected with HDV. • Symptoms are more severe in the second case. - since HBV has already established a replicative state, it allows HDV to replicate IMMEDIATELY • Causes direct cytopathic effects in liver (cirrhosis and "fulminant hepatitis").
Hepatitis E Virus
• Enteric virus that is spread predominantly by an oral-fecal route. • Resembles Calicivirus or "Norwalk Agent". • Symptoms similar to HAV, but has a higher mortality rate (1-2%). Mortality rate is even higher (~20%) in pregnant women. • Seen primarily in developing nations, sometimes at epidemic rates. • Does not establish chronic infection.
Hepatitis D Virus
• Has a circular, single stranded RNA genome. • Circular genome is surrounded by delta antigen. • Is spread in blood, semen and vaginal secretions (like HBV).
•Describe and note the temporal evolution of the Hepatitis B serological profiles and correlate the appearance of specific serum markers with disease stage and activity.
• Hepatitis B surface antigen (HBsAg): A protein on the surface of hepatitis B virus; it can be detected in high levels in serum during acute or chronic hepatitis B virus infection. The presence of HBsAg indicates that the person is infectious. The body normally produces antibodies to HBsAg as part of the normal immune response to infection. HBsAg is the antigen used to make hepatitis B vaccine. • Hepatitis B surface antibody (anti-HBs): The presence of anti-HBs is generally interpreted as indicating recovery and immunity from hepatitis B virus infection. Anti-HBs also develops in a person who has been successfully vaccinated against hepatitis B. • Total hepatitis B core antibody (anti-HBc): Appears at the onset of symptoms in acute hepatitis B and persists for life. The presence of anti-HBc indicates previous or ongoing infection with hepatitis B virus in an undefined time frame. • IgM antibody to hepatitis B core antigen (IgM anti-HBc): Positivity indicates recent infection with hepatitis B virus (<6 mos). Its presence indicates acute infection.
•Understand antiviral treatments for Hepatitis B and C. Hep B
• Immune Globulin: Can be used to prevent and/or ameliorate disease if given prior to, or early in the course of infection. • Interferon-a Can be used for treatment of chronic disease. Non-specific, and has side effects • Antiviral drugs that target the viral polymerase/reverse transcriptase (lamivudine, entecavir, telbivudine, tenofovir) or nucleoside analogues (adefovir, dipivoxil,famciclovir) can also be used to treat chronic disease. Taken for 1 year, but resistance can develop.
Hep C antiviral
• Initially treated with Interferon-alpha, alone or in combination with Ribavirin. • Ribavirin: A nucleoside analogue that inhibits nucleoside biosynthesis, mRNA capping, and RNA polymerases. • Combined therapy (Ifn plus Ribavirin) yielded recovery rates up to 50%. • New, direct-acting oral agents capable of curing chronic HCV were first approved in 2011. These include ritonavir, simeprevir, sofosbuvir, and others. They target viral proteins (replicase, protease, etc.) and can achieve cure rates of >90%
•Contrast gastroenteritis due to Norovirus and Rotavirus, as well current vaccine availability. Norovirus
• Norovirus is a leading cause of food-borne disease outbreaks in the United States - up to 21 million cases per year! • Spread by direct contact with an infected person or by touching a contaminated surface. • 3 out of 4 norovirus outbreaks occur in long-term care facilities like nursing homes, and elderly residents are more likely to get very sick from norovirus infections. • Large number of strains and high mutation rate allows reinfection despite previous exposure. • No specific treatment, prevent dehydration.