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a Virology 06 Hep 2


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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)
- 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
- 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
- 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

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