Broadly Neutralizing Antibody Mediated Clearance of Human Hepatitis C Virus Infection

Creators: Kinchen, Valerie J.; Zahid, Muhammad N.; Flyak, Andrew I.; Soliman, Mary G.; Learn, Gerald H.; Wang, Shuyi; Davidson, Edgar; Doranz, Benjamin J.; Ray, Stuart C.; Cox, Andrea L.; Crowe, James E., Jr.; Bjorkman, Pamela J.; Shaw, George M.; Bailey, Justin R.

Abstract

The role that broadly neutralizing antibodies (bNAbs) play in natural clearance of human hepatitis C virus (HCV) infection and the underlying mechanisms remain unknown. Here, we investigate the mechanism by which bNAbs, isolated from two humans who spontaneously cleared HCV infection, contribute to HCV control. Using viral gene sequences amplified from longitudinal plasma of the two subjects, we found that these bNAbs, which target the front layer of the HCV envelope protein E2, neutralized most autologous HCV strains. Acquisition of resistance to bNAbs by some autologous strains was accompanied by progressive loss of E2 protein function, and temporally associated with HCV clearance. These data demonstrate that bNAbs can mediate clearance of human HCV infection by neutralizing infecting strains and driving escaped viruses to an unfit state. These immunopathologic events distinguish HCV from HIV-1 and suggest that development of an HCV vaccine may be achievable.

Additional Information

© 2018 Elsevier Inc. Received 11 July 2018, Revised 17 August 2018, Accepted 24 September 2018, Available online 14 November 2018. The authors would like to thank Michelle Colbert and Alexander Gooden for technical support. This research was supported by NIH grants R01AI127469 (to J.R.B. and P.J.B.) and U19 AI088791 (to J.R.B., G.M.S., and A.L.C.), and NIH contract HHSN272201400058C (to B.J.D.). A.I.F. is a Cancer Research Institute Irvington Fellow supported by the Cancer Research Institute. Content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Author Contributions: J.R.B., A.L.C., and G.M.S. conceived the study; M.N.Z., G.H.L., S.W., and G.M.S. performed viral sequencing and sequence analysis; M.G.S. and A.L.C. performed T cell analysis; V.J.K. performed binding, neutralization, and viral fitness experiments; J.E.C. and A.I.F. provided antibodies; A.I.F. and P.J.B. solved crystal structures; E.D. and B.J.D. performed epitope mapping; V.J.K., A.I.F., S.C.R., A.L.C., G.M.S., and J.R.B. analyzed the data; V.J.K. and J.R.B. wrote the original draft; and all authors reviewed and edited the manuscript. Data and Software Availability: Viral sequences generated for this study are accessible from GenBank (GenBank: MH834650-MH835192). All other data that support the findings of this study are available from the Lead Contact upon request. Declaration of Interests: A.I.F., J.E.C., G.M.S., and J.R.B. are inventors of patents submitted pertaining to some of the antibodies and antigens presented in this paper. J.E.C. has served as a consultant for Takeda Vaccines, Sanofi Pasteur, Pfizer, and Novavax; is on the Scientific Advisory Boards of CompuVax, GigaGen, Meissa Vaccines, and PaxVax; and is Founder of IDBiologics, Inc. The other authors declare no competing interests.

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Accepted Version - nihms-1510957.pdf

Supplemental Material - 1-s2.0-S193131281830550X-mmc1.pdf

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