1887

Abstract

Hypervariable region 1 (HVR1) is one of the potential neutralization domains in the E2 glycoprotein of hepatitis C virus (HCV). Point mutations of the HVR1 can lead to humoral immune escape in HCV-infected patients. In this study, we segregated the chronically infected viraemic sera from HCV-infected patients into populations of antibody-free virus and antibody-associated virus (AAV) and mapped potential epitopes within the E1E2 gene junction of AAV sequences (residues 364–430). Furthermore, we generated HCV pseudoparticles (HCVpp) derived from AAV sequences to assess their infectivity. We studied the neutralization potential of virus-free Fab obtained from antibody–virus complexes, in the HCVpp system. We observed selective targeting of clonotypic HCV variants from the quasispecies pool. Moreover, we identified potential neutralizing epitopes within the HVR1 and an additional epitope that overlapped with a broadly neutralizing AP33 epitope (amino acid 412–423 in E2). We observed a marked difference in the infectivity of HCVpp generated using E1E2 sequences isolated from AAV. We document reduction in the infectivity of HCVpp-H77 and HCVpp derived from AAV sequences when challenged with virus-free Fab. Our results provide novel insights into the complexities of engagement between HCV and the humoral immune system.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.000659
2017-02-01
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/jgv/98/2/179.html?itemId=/content/journal/jgv/10.1099/jgv.0.000659&mimeType=html&fmt=ahah

References

  1. Wong JA, Bhat R, Hockman D, Logan M, Chen C et al. Recombinant hepatitis C virus envelope glycoprotein vaccine elicits antibodies targeting multiple epitopes on the envelope glycoproteins associated with broad cross-neutralization. J Virol 2014; 88:14278–14288 [View Article][PubMed]
    [Google Scholar]
  2. Allain JP, Dong Y, Vandamme AM, Moulton V, Salemi M. Evolutionary rate and genetic drift of hepatitis C virus are not correlated with the host immune response: studies of infected donor-recipient clusters. J Virol 2000; 74:2541–2549 [View Article][PubMed]
    [Google Scholar]
  3. Farci P, Shimoda A, Coiana A, Diaz G, Peddis G et al. The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies. Science 2000; 288:339–344 [View Article][PubMed]
    [Google Scholar]
  4. Guan M, Wang W, Liu X, Tong Y, Liu Y et al. Three different functional microdomains in the hepatitis C virus hypervariable region 1 (HVR1) mediate entry and immune evasion. J Biol Chem 2012; 287:35631–35645 [View Article][PubMed]
    [Google Scholar]
  5. Chhatwal J, Kanwal F, Roberts MS, Dunn MA. Cost-effectiveness and budget impact of hepatitis C virus treatment with sofosbuvir and ledipasvir in the United States. Ann Intern Med 2015; 162:397–406 [View Article][PubMed]
    [Google Scholar]
  6. Drummer HE. Challenges to the development of vaccines to hepatitis C virus that elicit neutralizing antibodies. Front Microbiol 2014; 5:329 [View Article][PubMed]
    [Google Scholar]
  7. Zeisel MB, Baumert TF. HCV entry and neutralizing antibodies: lessons from viral variants. Future Microbiol 2009; 4:511–517 [View Article][PubMed]
    [Google Scholar]
  8. Bailey JR, Wasilewski LN, Snider AE, El-Diwany R, Osburn WO et al. Naturally selected hepatitis C virus polymorphisms confer broad neutralizing antibody resistance. J Clin Invest 2015; 125:437–447 [View Article][PubMed]
    [Google Scholar]
  9. Pestka JM, Zeisel MB, Bläser E, Schürmann P, Bartosch B et al. Rapid induction of virus-neutralizing antibodies and viral clearance in a single-source outbreak of hepatitis C. Proc Natl Acad Sci USA 2007; 104:6025–6030 [View Article][PubMed]
    [Google Scholar]
  10. Thimme R, Oldach D, Chang KM, Steiger C, Ray SC et al. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med 2001; 194:1395–1406 [View Article][PubMed]
    [Google Scholar]
  11. Thimme R, Lohmann V, Weber F. A target on the move: innate and adaptive immune escape strategies of hepatitis C virus. Antiviral Res 2006; 69:129–141 [View Article][PubMed]
    [Google Scholar]
  12. Lavie M, Goffard A, Dubuisson J. HCV glycoproteins: assembly of a functional E1–E2 heterodimer. In Tan SL. (editor) Hepatitis C Viruses: Genomes and Molecular Biology Norfolk, UK: Horizon Bioscience; 2006
    [Google Scholar]
  13. Ray R, Meyer K, Banerjee A, Basu A, Coates S et al. Characterization of antibodies induced by vaccination with hepatitis C virus envelope glycoproteins. J Infect Dis 2010; 202:862–866 [View Article][PubMed]
    [Google Scholar]
  14. Vieyres G, Dubuisson J, Patel AH. Characterization of antibody-mediated neutralization directed against the hypervariable region 1 of hepatitis C virus E2 glycoprotein. J Gen Virol 2011; 92:494–506 [View Article][PubMed]
    [Google Scholar]
  15. Law M, Maruyama T, Lewis J, Giang E, Tarr AW et al. Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge. Nat Med 2008; 14:25–27 [View Article][PubMed]
    [Google Scholar]
  16. Doria-Rose NA, Schramm CA, Gorman J, Moore PL, Bhiman JN et al. Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies. Nature 2014; 509:55–62 [View Article][PubMed]
    [Google Scholar]
  17. Qiu X, Wong G, Audet J, Bello A, Fernando L et al. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature 2014; 514:47–53 [View Article][PubMed]
    [Google Scholar]
  18. Stiegler G, Katinger H. Therapeutic potential of neutralizing antibodies in the treatment of HIV-1 infection. J Antimicrob Chemother 2003; 51:757–759 [View Article][PubMed]
    [Google Scholar]
  19. Ray SC, Fanning L, Wang XH, Netski DM, Kenny-Walsh E et al. Divergent and convergent evolution after a common-source outbreak of hepatitis C virus. J Exp Med 2005; 201:1753–1759 [View Article][PubMed]
    [Google Scholar]
  20. Dejnirattisai W, Supasa P, Wongwiwat W, Rouvinski A, Barba-Spaeth G et al. Dengue virus sero-cross-reactivity drives antibody-dependent enhancement of infection with zika virus. Nat Immunol 2016; 17:1102–1108 [View Article][PubMed]
    [Google Scholar]
  21. Basavapathruni A, Yeh WW, Coffey RT, Whitney JB, Hraber PT et al. Envelope vaccination shapes viral envelope evolution following simian immunodeficiency virus infection in rhesus monkeys. J Virol 2010; 84:953–963 [View Article][PubMed]
    [Google Scholar]
  22. Dowd KA, Netski DM, Wang XH, Cox AL, Ray SC. Selection pressure from neutralizing antibodies drives sequence evolution during acute infection with hepatitis C virus. Gastroenterology 2009; 136:2377–2386 [View Article][PubMed]
    [Google Scholar]
  23. Palmer BA, Moreau I, Levis J, Harty C, Crosbie O et al. Insertion and recombination events at hypervariable region 1 over 9.6 years of hepatitis C virus chronic infection. J Gen Virol 2012; 93:2614–2624 [View Article][PubMed]
    [Google Scholar]
  24. Palmer BA, Schmidt-Martin D, Dimitrova Z, Skums P, Crosbie O et al. Network analysis of the chronic Hepatitis C virome defines HVR1 evolutionary phenotypes in the context of humoral immune responses. J Virol 2015; 90:3318–3329 [CrossRef]
    [Google Scholar]
  25. Bartosch B, Dubuisson J, Cosset FL. Infectious hepatitis C virus pseudo-particles containing functional E1–E2 envelope protein complexes. J Exp Med 2003; 197:633–642 [View Article][PubMed]
    [Google Scholar]
  26. Giang E, Dorner M, Prentoe JC, Dreux M, Evans MJ et al. Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus. Proc Natl Acad Sci USA 2012; 109:6205–6210 [View Article][PubMed]
    [Google Scholar]
  27. Meunier JC, Russell RS, Goossens V, Priem S, Walter H et al. Isolation and characterization of broadly neutralizing human monoclonal antibodies to the e1 glycoprotein of hepatitis C virus. J Virol 2008; 82:966–973 [View Article][PubMed]
    [Google Scholar]
  28. Tarr AW, Owsianka AM, Szwejk A, Ball JK, Patel AH. Cloning, expression, and functional analysis of patient-derived hepatitis C virus glycoproteins. Methods Mol Biol 2007; 379:177–197 [View Article][PubMed]
    [Google Scholar]
  29. Moreau I, O'Sullivan H, Murray C, Levis J, Crosbie O et al. Separation of hepatitis C genotype 4a into IgG-depleted and IgG-enriched fractions reveals a unique quasispecies profile. Virol J 2008; 5:103 [View Article][PubMed]
    [Google Scholar]
  30. Owsianka A, Tarr AW, Juttla VS, Lavillette D, Bartosch B et al. Monoclonal antibody AP33 defines a broadly neutralizing epitope on the hepatitis C virus E2 envelope glycoprotein. J Virol 2005; 79:11095–11104 [View Article][PubMed]
    [Google Scholar]
  31. Palmer BA, Schmidt-Martin D, Dimitrova Z, Skums P, Crosbie O et al. Network analysis of the chronic hepatitis C virome defines hypervariable region 1 evolutionary phenotypes in the context of humoral immune responses. J Virol 2015; 90:3318–3329 [View Article][PubMed]
    [Google Scholar]
  32. Naik AS, Palmer BA, Crosbie O, Kenny-Walsh E, Fanning LJ. A single amino acid change in the hypervariable region 1 of hepatitis C virus genotype 4a aids humoral immune escape. J Gen Virol 2016; 97:1345–1349 [View Article][PubMed]
    [Google Scholar]
  33. Palmer BA, Dimitrova Z, Skums P, Crosbie O, Kenny-Walsh E et al. Analysis of the evolution and structure of a complex intrahost viral population in chronic hepatitis C virus mapped by ultradeep pyrosequencing. J Virol 2014; 88:13709–13721 [View Article][PubMed]
    [Google Scholar]
  34. Derrick JP, Wigley DB. The third IgG-binding domain from streptococcal protein G. An analysis by X-ray crystallography of the structure alone and in a complex with Fab. J Mol Biol 1994; 243:906–918 [View Article][PubMed]
    [Google Scholar]
  35. Kenny-Walsh E. Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. Irish Hepatology Research Group. N Engl J Med 1999; 340:1228–1233 [View Article][PubMed]
    [Google Scholar]
  36. Helle F, Duverlie G, Dubuisson J. The hepatitis C virus glycan shield and evasion of the humoral immune response. Viruses 2011; 3:1909–1932 [View Article][PubMed]
    [Google Scholar]
  37. Ball JK, Tarr AW, McKeating JA. The past, present and future of neutralizing antibodies for hepatitis C virus. Antiviral Res 2014; 105:100–111 [View Article][PubMed]
    [Google Scholar]
  38. Gerotto M, Dal Pero F, Loffreda S, Bianchi FB, Alberti A et al. A 385 insertion in the hypervariable region 1 of hepatitis C virus E2 envelope protein is found in some patients with mixed cryoglobulinemia type 2. Blood 2001; 98:2657–2663 [View Article][PubMed]
    [Google Scholar]
  39. Cashman SB, Marsden BD, Dustin LB. The humoral immune response to HCV: understanding is key to vaccine development. Front Immunol 2014; 5:550 [View Article][PubMed]
    [Google Scholar]
  40. Deng K, Liu R, Rao H, Jiang D, Wang J et al. Antibodies targeting novel neutralizing epitopes of hepatitis C virus glycoprotein preclude genotype 2 virus infection. PLoS One 2015; 10:e0138756 [View Article][PubMed]
    [Google Scholar]
  41. Bankwitz D, Steinmann E, Bitzegeio J, Ciesek S, Friesland M et al. Hepatitis C virus hypervariable region 1 modulates receptor interactions, conceals the CD81 binding site, and protects conserved neutralizing epitopes. J Virol 2010; 84:5751–5763 [View Article][PubMed]
    [Google Scholar]
  42. Bartosch B, Vitelli A, Granier C, Goujon C, Dubuisson J et al. Cell entry of hepatitis C virus requires a set of co-receptors that include the CD81 tetraspanin and the SR-B1 scavenger receptor. J Biol Chem 2003; 278:41624–41630 [View Article][PubMed]
    [Google Scholar]
  43. Prentoe J, Jensen TB, Meuleman P, Serre SB, Scheel TK et al. Hypervariable region 1 differentially impacts viability of hepatitis C virus strains of genotypes 1 to 6 and impairs virus neutralization. J Virol 2011; 85:2224–2234 [View Article][PubMed]
    [Google Scholar]
  44. Sautto G, Tarr AW, Mancini N, Clementi M. Structural and antigenic definition of hepatitis C virus E2 glycoprotein epitopes targeted by monoclonal antibodies. Clin Dev Immunol 2013; 2013:450963 [View Article]
    [Google Scholar]
  45. Tarr AW, Khera T, Hueging K, Sheldon J, Steinmann E et al. Genetic diversity underlying the envelope glycoproteins of hepatitis C virus: structural and functional consequences and the implications for vaccine design. Viruses 2015; 7:3995–4046 [View Article][PubMed]
    [Google Scholar]
  46. Mullan B, Sheehy P, Shanahan F, Fanning L. Do Taq-generated RT-PCR products from RNA viruses accurately reflect viral genetic heterogeneity?. J Viral Hepat 2004; 11:108–114 [View Article][PubMed]
    [Google Scholar]
  47. Posthumus WP, Lenstra JA, Van Nieuwstadt AP, Schaaper WM, Van der Zeijst BA et al. Immunogenicity of peptides simulating a neutralization epitope of transmissible gastroenteritis virus. Virology 1991; 182:371–375 [View Article][PubMed]
    [Google Scholar]
  48. Langedijk JP, Brandenburg AH, Middel WG, Osterhaus A, Meloen RH et al. A subtype-specific peptide-based enzyme immunoassay for detection of antibodies to the G protein of human respiratory syncytial virus is more sensitive than routine serological tests. J Clin Microbiol 1997; 35:1656–1660[PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.000659
Loading
/content/journal/jgv/10.1099/jgv.0.000659
Loading

Data & Media loading...

Supplements

Supplementary File 1

PDF
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error