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T-ce ll Immunity to the Hepatitis C Virus During and After Pregnancy

T-ce ll Immunity to the Hepatitis C Virus During and After Pregnancy. BCMM AND VACCINES & IMMUNITY JOINT MEETING Sept 2, 2011. C. E1. E2. p7. NS2. NS3. a NS4 b. a NS5 b. Core. Serine protease Helicase. ≈3000 aa. RNA dependent RNA polymerase. Protease Cofactor. Envelope

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T-ce ll Immunity to the Hepatitis C Virus During and After Pregnancy

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  1. T-cell Immunity to the Hepatitis C Virus During and After Pregnancy BCMM AND VACCINES & IMMUNITY JOINT MEETING Sept 2, 2011

  2. C E1 E2 p7 NS2 NS3 aNS4b aNS5b Core Serine protease Helicase ≈3000 aa RNA dependent RNA polymerase Protease Cofactor Envelope Glycoproteins F Hepatitis C Virus • Small, positive-stranded RNA virus • Prototype virus within the Hepacivirus genus of the Flaviviridae • 6 Genotypes, multiple subtypes • Genotype 1 is the most common and the most resistant to treatment

  3. Outcome of HCV Infection Resolved Infection (25%) Normal Liver Acute Infection Chronic Infection (75%) Chronic Hepatitis Cirrhosis (20%) Carcinoma (1-4% per year) Rapid Progression Alcohol use, coinfection ≤ 20 years Slow Progression Female sex, young age at infection ≥ 30 years - HCV related liver diseases – now the leading cause for liver transplantation in developed world Adapted from Lauer G & Walker B. NEJM 2001;345:41-52

  4. T-cell Immunity to HCV in Acute Resolving vs Persisting Infection serum antibodies Transaminase (liver cell death) Viremia Viremia CD8+ T cells (blood) CD8+ T cells (blood) CD4+ T cells (blood) CD4+ T cells (blood) ~25% 2 6 12 24 ~75% Rapid Resolution serum antibodies Persistent Infection 2 6 12 24 years weeks

  5. T-Lymphocytes: Adaptive Immune Cells Randomly generated receptors - Repertoire of 2*107 distinct T-cell receptors in peripheral blood Recognize foreign peptides presented by MHC molecules on cell surfaces CD8+ Cytotoxic T-cells: Target peptides from endogenous proteins on infected cells Kill infected cells CD4+ Helper T-cells: Target peptides from exogenous proteins presented by professional antigen presenting cells Secrete antiviral cytokines and augment function of CD8+ T-cells and B-cells (Nikolich-Zugich et al. Nat Rev Imm. 2004; 4:123-132)

  6. T-cell Success in Resolving HCV HCV-specific CD8+ T-cell T-cell Receptor Antiviral cytokines inhibit viral replication & cytotoxic chemicals kill infected cells HCV Peptide Class I MHC Molecule HCV-Infected Hepatocyte

  7. T-cell Failure in Chronic HCV Low Frequency T-cell exhaustion Escape mutation Poor Proliferation HCV-specific CD8+ T-cell HCV-specific CD8+ T-cell Reduced cytotoxicity and antiviral cytokine secretion Inhibitory co-receptors (PD-1, CTLA4, Tim-3) Mutated HCV Epitope HCV-Infected Hepatocyte HCV-Infected Hepatocyte

  8. Weak HCV-specific T-cell responses in chronic infection HCV 1b Peptide Set Core E1 E2 P7 NS2 NS3 aNS4b aNS5b CMV pp65 DMSO control Ex-vivo IFN-γ ELISpot 200,000 PBMCs/well

  9. Antepartum Delivery 3 mo 6 mo 18 mo Maternal Samples infant Samples OSU-NCH Hepatitis C Virus Immunity in Women and Children Study

  10. Influence of Pregnancy on Hepatitis C Viral Load M001: Genotype 2b. Age at 1st delivery: 26 yrs. Estimated duration of infection prior to 1st delivery: 12 yrs. M003: Genotype 1a. Age at 1st delivery: 34 yrs. Estimated duration of infection prior to 1st delivery: 0.6 yrs. M016: Genotype 2a. Age at 1st delivery: 24 yrs. Estimated duration of infection prior to 1st delivery: 4.7 yrs.

  11. Influence of Pregnancy on Hepatitis C Viremia Prepregnancy Pregnancy Postpartum Viremia CD8+ Function CD4+ Function Years Hypothesis: Resurgent HCV-specific T-cell immunity after delivery mediates the drop in viremia.

  12. Postpartum Viral Load Decline Associated with Broadening of HCV-Specific T-cell Response after Delivery

  13. Resurgence of Polyfunctional CD4+ T-cells Subject M001

  14. Define the Immunological Signature of Postpartum Viral Control Pregnancy Postpartum Postpartum Viral Control Stable Viremia • Function & Phenotype of HCV-specific T-cells • (Proliferation, Cytokine Secretion, Survival and Inhibitory Receptor Expression) • HCV-specific T-cell Receptor Analysis • (Diversity, Avidity) • Serum Cytokine Profile • Gene-expression profile of HCV-specific T-cells

  15. Influence of Pregnancy on HCV Evolution HCV genome mutates readily • 1012 virions produced daily • RNA-dependent RNA polymerase lacks proofreading function HCV mutates to escape CD8+ T-cell pressure • 50-70% of targeted class I epitopes mutate to escape T-cell responses • Appearance of escape mutations linked to failure to clear viremia • Some escape mutations impair replicative fitness and revert to wild-type when transferred to other individuals Hypothesis: Enhanced CD8+ T-cell pressure after delivery will cause accelerated viral evolution

  16. Viral Sequencing Through Consecutive Pregnancies Subject M003

  17. Viral Sequencing Through Consecutive Pregnancies Study week -6 Preg #1 0 25 Preg #2 40 56 66 86 152 Vertical lines represent amino acid substitutions relative to week -6 consensus sequence. Height of lines proportionate to fraction of clones bearing mutant residue.

  18. Viral Evolution Accelerates After Both Pregnancies

  19. Reversion of Mutation During 2nd Pregnancy Study week -6 Preg #1 0 25 Preg #2 40 56 66 86 152

  20. Mutations in overlapping T-cell epitopes permit escape from T-cell pressure M003 1402/9 M003 1395/9 (*Adjusted for transfection efficiency)

  21. Infectious HCV cell culture virus H77S.3 bearing “wild-type” week -6 sequence is more replicatively fit than virus bearing the escape mutant sequences. RNA Replication Infectious Virus Production “wk -6 wild-type sequence”

  22. Influence of Pregnancy on HCV Evolution Prepregnancy Pregnancy Postpartum B Viremia CD8+ Selection Pressure Viral Replicative Fitness A A: Reversion of escape mutations B: Re-emergence of previous +/- appearance of new escape mutations C: Compensatory mutations C Years • Aim 2. Define patterns of HCV evolution during and after pregnancy. • Determine if reduced virus replication after pregnancy is associated with an increased frequency of escape mutations in class I epitopes. • Determine the fitness cost of non-synonymous viral escape mutations that are lost during pregnancy. • Rationale. • Provides an independent virologic readout of intrahepatic CD8+ T-cell selection pressure to address the important question of whether HCV-specific T-cells can be functionally restored • Provide insight into the replicative fitness of viral quasispecies passed vertically in mother to child transmission, the most common route of pediatric HCV infection

  23. Pregnancy and other Persistent Viral Infections HBV HIV No significant change in viral load during or after pregnancy Burns et al. Am J Obstet Gynecol 1998; 178:355-9 Melvin et al. J Acquir Immune Defic Syndr 1997; 14:232-236 Garcia et al. N Engl J Med 1999;341:394-402 • Mean HBV DNA levels rise in pregnancy and fall in the postpartum period • ter Borg et al. J Viral Hepat 2008; 15:37-41 • 5 of 31 HBeAg+ women became HBeAg- in the postpartum period compared to 0 of 30 non-pregnant women. • Lin et al. J Med Virol 1989; 29:1-6 T1 or T2 24 mo PP T3 2 mo PP 12 mo PP ter Borg et al. Burns et al.

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