Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
30 Cards in this Set
- Front
- Back
HCV structure
|
-C is nucleocapsid protein
- E1 and E2 are glycoproteins present in the viral envelope - NS include proteases, and an RNA dependent RNA polymerase - substantial genetic heterogeneity - six genotypes (1, 2 and 3 are most prevalent in the US) and 100 subtypes |
|
HCV genome
|
- + sense ssRNA
- no 5’ cap; IRES in 5’ NTR - no virion-associated polymerase - one ORF translated as one polyprotein then cleaved by cellular and viral proteases |
|
HCV Clinical Features
|
- like acute HBV infection w/ lower serum ALT
- often sequential ‘episodes’ - many asymptomatic infections - 40% of chronic carriers later develop cirrhosis which progresses into carcinoma |
|
HCV pathogenesis
|
- damage to hepatocytes is apparently from cytotoxic T's and virus-induced cell death
- biopsies show most cells w/ no CPE, no HCV Ag or RNA, but bile duct damage, steatosis and lymphoid follicles - IFN response key for viral clearance - most become chronic, leading cause of chronic cirrhosis and requests for liver transplant - causes PHC - 40+% die |
|
HCV immunity
|
- virus undergoes “antigenic drift” within the patient - specific ab's promote the selective propagation of virus with variant antigens.
- “Quasi-species” concept. - positive serology(for anti-HCV) means on-going infection and viremia: not recovery |
|
HCV epi
|
- humans reservoir - ~1%
- blood-borne pathogen - ~80% prevalence in IV drug users - drugs, sex, childbirth, transfusion - blood banks now routinely use serology and an additional RT-PCR test - RF;s tattos and piercings - Sexual and vertical transmissions occur less frequently than with HBV |
|
HCV diagnosis
|
- Use ELISA for Ab's
- RT-PCR for viral RNA is now available |
|
HCV treatment
|
- No vaccine
- No hyperimmune serum - IFNα licensed for therapy experience is mixed - can achieve suppression of viremia (rebounds after stopping therapy) - new aggressive combo is interferon (injections) + ribavirin (oral) for 48 weeks -> ~40% have non-viremic with normal serum ALT esp for Genotypes 2 and 3 |
|
HBV genome
|
- circular pdsDNA(+strand=incomplete), w/ 4 overlaping ORFs w/ no non-coding bases
- 2 in-frame start codons -> Pre C, the signal peptide, is cleaved within Pre C And near the carboxyl terminus of C -> HBe - Viral polymerase has priming domain, RTase, & RNase H and does RT w/in nucleocapsid - X gene encodes regulatory protein (not involved w/ viron |
|
HBV structure
|
- the HBcAg is capsid protein
- HBe is similar but distinct - 3 in-frame start codons make Surface/viral envelope - L (large) M S envelope proteins -L=Pre S1+pre S2+S, M=Pre S2+S, S=S - Mosly S, but most induced anti-HBs antibody is directed at epitopes in S, but can bind to all 3 - Most HBs in blood is small & spherical w/no nucleocapsid - 1st discovered “Australia ag” - not invecious, sub-unit vaccine idea - virion aka Dane particle; found at lower []s than HBs |
|
HBV viral replication
|
- gapped virion DNA is completed -> to nucleus -> covalently closed circular duplex DNA (ccc DNA)
- ccc DNA exists as a plasmid(NOT integrated - ccc DNA transcribed by host DNA dependent RNA polymerase II - Subgenomic mRNAs synthesized for protein synthesis In Cytoplasm - a genome-sized replicative RNA (pregenome) is synthesized - pregenom packaged into HBcAg->nucleocapsid - viral polymerase protein packaged (primer + RTase + RNaseH) - RT in cytoplasm occurs - This creates a nucleocapsid w/ dsDNA (and not RNA) |
|
HBV clinical course
|
- 1o infections asymptomatic
- In children, mostly asymptomatic w/ high rate of chronic carriage - if immunosup, always asymptomatic and persistent - longer incubation prior to symptoms than HAV or acute HCV - Chronic may develop, CPH, CAH, PHC - staging by biopsy - CAH → cirrhosis → PHC 2-30+ years - Antigen-antibody complexes ⇒ polyarteritis, glomeruneph. - range from subclinical ⇒ fatal acute fulminant - anti-HBeAbs is a good sign, along w/ viremia, less replication in liver, lesser rate of immune-mediated damage to liver |
|
HBV Pathogenesis
|
- regulates replication level in each hepatocyte so cell isn't overstressed
- no cytopathology is apparent(cell=fully functional) - replicates to very high levels in HIV w/o hepatitis - For HBV caused PHC, 80% of tumors have integrated HBV DNA - low level of infection at specific extra-hepatic sites(bile duct epi, pancreas, spleen, kidney, lymphocytes) - a mutant type is more fulminant and has HBe negative phenotype and serology |
|
HBV Immunity
|
- specific CTLs, directed probably at HBc and/or HBe Ags
- Persistent infection can resolve, along w/ anti-HBsAbs so liver damage ends |
|
HBV primary infection
|
1 - acute episode - strong immune response → clearance, recovery, no persistence, lifelong immunity (anti-HBsAb)
2 - acute episode, intermediate immune response → persistent infection → chronic liver disease 3 - no acute disease, asymptomatic → persistent infection (healthy carrier) → tolerance erodes → chronic liver disease - In healthy carriers no activated (HBV specific) CTLs. CTLs seem “anergic”. |
|
HBV epi
|
- 400 million carriers, esp in Asia, sub-Saharan, Aleuts, Am. Indians, and Polynesians
- intermediate prevalence in Mediterranean countries(S euro, N africa) - lower prev in western Europe and Caucasian Americans (mainly via STD) - moms can pass on so screen - teens and college at most risk - highest titer in blood, but in spit and semen |
|
HBV Diagnosis
|
- serology
- if acute, rise in HBs Ag in acute infection then gradual decline, (immune response-late rise anti-HBs ag) - window period is when HBs Ag has disappeared, but anti-HBs Ab hasn't appeared - only sign is anti-HBc antigen - if chronic, the HBsAg rise during acute is maintained - accute can be un-noticed |
|
HBV vaccination
|
- subunit vaccine is recombinant HBs Ag
- universal vaccination of newborns - birth, 1 month, 6 months - if job has infection risk - immediate, 1 month, 6 months - effective post-exposure if given within one week - newborns of +mom get HBIG immediately (passive) - exposed can get passive immun. |
|
HBV treatment
|
- IFN for non-Asians
- Lamivudine (3TC) - Adefovir - Lamivudine + penciclovir - cant use AZT (conjugates in liver w/ glucuronic acid at 5' OH group, prevents host kinase from activating it) - can't use proteases (HBV doesn't encode viral protease) |
|
Adefovir
|
- treats HBV
- acyclic nucleotide analog of dAMP - ring more flexible - converted first to mono then to di-phosphate which is dATP analog(ACTIVE) - terminates chain of HBV DNA synthesis |
|
Lamivudine
|
- 3TC, treats HBV
- blocks viremia, but most cases rebound in post-drug setting - long term benefit uncertain |
|
Lamivudine and penciclovir
|
- chain-terminators, treat HBV
- used in liver transplant pts - drug-resistant strains emerge due to mutations in HBV RT |
|
HDV genome
|
- small, circular ssRNA virus
- no genes for envelope or replicating - replicates only in host cells HBV co-infected - 1 ORF for HD Ag (internal core protein) - (-) sense, so unique b/c it does NOT encode RNA-dependent RNA-polymerase - uses host DNA dependent RNA polymerase II |
|
HDV structure
|
- RNA formed into a fragile nucleocapsid with the HD Ag
- parasitizes envelope from HBV lipoprotein - The viral RNA is also a ribozyme - can self cleave, and ligate |
|
HDV clinical features
|
if co-infection with HBV, there is a more aggressive clinical course with higher mortality
|
|
HDV pathogenesis
|
- Two infection settings
1) Naive pts get both HBV and HDV simultaneously -> acute episodes of both, first HBV, then HDV -> high, transient viremia 2) HBV carrier gets HDV as a superinfection -> chronic forms of both |
|
HDV immune response
|
- Acute vs chronic is determined by immune response to HBV
- If the immune system clears HBV from the liver, it also clears HDV |
|
HDV Epi
|
- Transmission probably like HBV
- In the US, outbreaks in IV drug users who share needles |
|
HDV diagnosis
|
- Detect either HD antigen or antibody to HD antigen
|
|
HDV treatment
|
- No specific treatment or vaccination
- Vaccination for HBV protects against HDV - Lamivudine or penciclovir will inhibit HBV RT process, but NOT synthesis of HBs Ag - so they wont affect the course of HDV infection |