Hepatitis C Virus–Escape Studies for Human Monoclonal Antibody AR4A Reveal Isolate-Specific Resistance and a High Barrier to Resistance. (9th August 2018)

• Record Type: Journal Article
• Authors: Velázquez-Moctezuma, Rodrigo; Galli, Andrea; Law, Mansun; Bukh, Jens; Prentoe, Jannick
• Is Part Of: Journal of infectious diseases. Volume 219:Number 1(2019)
• Page Start: 68
• Page End: 79
• Publication Date: 2018-08-09
• Subjects: HCV -- HVR1 -- hypervariable region 1 -- vaccine -- immune evasion -- antibody escape -- liver disease; Communicable diseases -- Periodicals; Diseases -- Causes and theories of causation -- Periodicals; Medicine -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.9
• DOI: 10.1093/infdis/jiy481
• Languages: English
• ISSNs: 0022-1899

Abstract

Abstract: Global control of hepatitis C virus (HCV) depends on development of a prophylactic vaccine. We studied escape for cross-genotype–reactive neutralizing antibody AR4A, providing valuable information for HCV vaccine design. We cultured HCV core-NS2 recombinants H77 (genotype 1a)/JFH1 or the highly antibody-susceptible hypervariable region 1 (HVR1)–deleted variants H77/JFH1∆HVR1 and J6(genotype 2a)/JFH1∆HVR1 in Huh7.5 cells with AR4A. Long-term AR4A exposure of H77/JFH1 and H77/JFH1∆HVR1 did not yield resistance. However, J6/JFH1∆HVR1 developed the envelope-E2 substitutions I696T or I696N, which reduced AR4A binding (I696N > I696T). I696N conferred greater AR4A resistance than I696T in J6/JFH1∆HVR1, whereas the reverse was observed in J6/JFH1. This was because I696N but not I696T conferred broadly increased antibody neutralization susceptibility to J6/JFH1. I696N and I696T abrogated infectivity of H77/JFH1 and broadly increased neutralization susceptibility of S52 (genotype 3a)/JFH1. In conclusion, I696 is in the AR4A epitope, which has a high barrier to resistance, thus strengthening the rationale for its inclusion in rational HCV vaccine designs. Abstract : A hepatitis C virus (HCV) vaccine is urgently needed. The AR4A human monoclonal antibody targets a cross-genotype conserved HCV envelope epitope with potential relevance for vaccine development. We identify AR4A resistance substitutions and demonstrate a high barrier to AR4A resistance.