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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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@article{c0efc7cab77c44bc93182a97fff0e9ad,
title = "Hepatitis C virus escape studies for human monoclonal antibody AR4A reveal isolate-specific resistance and a high barrier to resistance",
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 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.",
keywords = "antibody escape, HCV, HVR1, hypervariable region 1, immune evasion, liver disease, vaccine",
author = "Rodrigo Vel{\'a}zquez-Moctezuma and Andrea Galli and Mansun Law and Jens Bukh and Jannick Prentoe",
year = "2019",
month = "1",
day = "1",
doi = "10.1093/infdis/jiy481",
language = "English",
volume = "219",
pages = "68--79",
journal = "Journal of Infectious Diseases",
issn = "0022-1899",
publisher = "University of Chicago Press",
number = "1",

}

RIS

TY - JOUR

T1 - Hepatitis C virus escape studies for human monoclonal antibody AR4A reveal isolate-specific resistance and a high barrier to resistance

AU - Velázquez-Moctezuma, Rodrigo

AU - Galli, Andrea

AU - Law, Mansun

AU - Bukh, Jens

AU - Prentoe, Jannick

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - antibody escape

KW - HCV

KW - HVR1

KW - hypervariable region 1

KW - immune evasion

KW - liver disease

KW - vaccine

UR - http://www.scopus.com/inward/record.url?scp=85058478102&partnerID=8YFLogxK

U2 - 10.1093/infdis/jiy481

DO - 10.1093/infdis/jiy481

M3 - Journal article

VL - 219

SP - 68

EP - 79

JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

SN - 0022-1899

IS - 1

ER -

ID: 54975628