Department of Molecular Virology, National AIDS Research Institute, Indian Council of Medical Research, Bhosari, Pune, India.
PLoS One. 2012;7(5):e37157. doi: 10.1371/journal.pone.0037157. Epub 2012 May 14.
HIV-1 variants that show unusual sensitivity to autologous antibodies due to presence of critical neutralization signatures would likely contribute towards rational envelope based HIV-1 vaccine design. In the present study, we found that presence of a naturally occurring H681 in gp41 membrane proximal external region (MPER) of a clade C envelope (Env) obtained from a recently infected Indian patient conferred increased sensitivity to autologous and heterologous plasma antibodies. Furthermore, Env-pseudotyped viruses expressing H681 showed increased sensitivity to soluble CD4, b12 and 4E10 monoclonal antibodies both in related and unrelated Envs and was corroborated with increased Env susceptibility and binding to cellular CD4 as well as with prolonged exposure of MPER epitopes. The increased gp120-CD4 interaction was further associated with relative exposure of CD4-induced epitopes and macrophage infectivity. In summary, our data indicate that Y681H substitution exposes neutralizing epitopes in CD4bs and MPER towards comprehensive interference in HIV-1 entry.
由于存在关键的中和表位，对自身抗体表现出异常敏感性的 HIV-1 变体可能有助于基于包膜的 HIV-1 疫苗的合理设计。在本研究中，我们发现，在最近感染的印度患者的 clade C 包膜（Env）的 gp41 膜近端外部区域（MPER）中存在天然存在的 H681，使自身和异源血浆抗体的敏感性增加。此外，表达 H681 的 Env 假型病毒在相关和不相关的 Env 中对可溶性 CD4、b12 和 4E10 单克隆抗体的敏感性增加，并与增加的 Env 易感性和与细胞 CD4 的结合以及 MPER 表位的延长暴露相吻合。增加的 gp120-CD4 相互作用进一步与 CD4 诱导表位的相对暴露和巨噬细胞感染性相关。总之，我们的数据表明，Y681H 取代使 CD4bs 和 MPER 中的中和表位暴露，从而对 HIV-1 进入进行全面干扰。
