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Hepatitis C virus escape studies for human monoclonal antibody AR4A reveal isolate-specific resistance and a high barrier to resistance

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DOI

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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 δHVR1 and J6(genotype 2a)/JFH1 δHVR1 in Huh7.5 cells with AR4A. Long-term AR4A exposure of H77/JFH1 and H77/JFH1 δHVR1 did not yield resistance. However, J6/JFH1 δHVR1 developed the envelope-E2 substitutions I696T or I696N, which reduced AR4A binding (I696N > I696T). I696N conferred greater AR4A resistance than I696T in J6/JFH1 δHVR1, 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.

OriginalsprogEngelsk
TidsskriftThe Journal of infectious diseases
Vol/bind219
Udgave nummer1
Sider (fra-til)68-79
Antal sider12
ISSN0022-1899
DOI
StatusUdgivet - 1 jan. 2019

ID: 54975628