Hepatitis C Virus-Escape Studies for Human Monoclonal Antibody AR4A Reveal Isolate-Specific Resistance and a High Barrier to Resistance.
Hepatitis C Virus-Escape Studies for Human Monoclonal Antibody AR4A Reveal Isolate-Specific Resistance and a High Barrier to Resistance.
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人单克隆抗体 AR4A 的丙型肝炎病毒逃逸研究揭示了分离株特异性耐药性和高耐药性屏障。
DOI：
10.1093/infdis/jiy481
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Prentoe,Jannick
中科院分区：
文献类型：
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作者：
Velázquez-Moctezuma,Rodrigo;Galli,Andrea;Law,Mansun;Bukh,Jens;Prentoe,Jannick
丙型肝炎病毒（HCV）的全球控制取决于预防性疫苗的开发。研究了跨基因型反应性中和抗体AR 4A的逃逸，为HCV疫苗设计提供了有价值的信息。我们在含有AR 4A的Huh 7.5细胞中培养HCV核心-NS 2重组体H77（基因型1a）/JFH 1或高度抗体敏感的高变区1（HVR 1）缺失变体H77/JFH 1 → HVR 1和J6（基因型2a）/JFH 1 → HVR 1。H77/JFH 1和H77/JFH 1 HVR 1的长期AR 4A暴露未产生耐药性。然而，J6/JFH 1 HVR 1产生了E2的I696 T或I696 N取代，这降低了AR 4A的结合（I696 N> I696 T）。在J6/JFH 1中，I696 N比I696 T赋予更大的AR 4A抗性，而在J6/JFH 1中观察到相反的情况。这是因为I696 N而不是I696 T赋予了对J6/JFH 1的广泛增加的抗体中和敏感性。I696 N和I696 T消除了H77/JFH 1的感染性，并广泛增加了S52（基因型3a）/JFH 1的中和敏感性。总之，I696位于AR 4A表位中，其具有高耐药屏障，从而加强了将其纳入合理HCV疫苗设计的理由。
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∆HVR1and J6(genotype 2a)/JFH1∆HVR1in Huh7.5 cells with AR4A. Long-term AR4A exposure of H77/JFH1 and H77/JFH1∆HVR1did not yield resistance. However, J6/JFH1∆HVR1developed 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.