Centre de Recherche du CHUM, Montreal, Quebec, Canada.
Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, Canada.
J Virol. 2019 Oct 29;93(22). doi: 10.1128/JVI.01403-19. Print 2019 Nov 15.
CD4 downregulation on infected cells is a highly conserved function of primate lentiviruses. It has been shown to positively impact viral replication by a variety of mechanisms, including enhanced viral release and infectivity, decrease of cell reinfection, and protection from antibody-dependent cellular cytotoxicity (ADCC), which is often mediated by antibodies that require CD4 to change envelope (Env) conformation. Here, we report that incorporation of CD4 into HIV-1 viral particles affects Env conformation resulting in the exposure of occluded epitopes recognized by CD4-induced antibodies. This translates into enhanced neutralization susceptibility by these otherwise nonneutralizing antibodies but is prevented by the HIV-1 Nef accessory protein. Altogether, these findings suggest that another functional consequence of Nef-mediated CD4 downregulation is the protection of viral particles from neutralization by commonly elicited CD4-induced antibodies. It has been well established that Env-CD4 complexes expose epitopes recognized by commonly elicited CD4-induced antibodies at the surface of HIV-1-infected cells, rendering them vulnerable to ADCC responses. Here, we show that CD4 incorporation has a profound impact on Env conformation at the surface of viral particles. Incorporated CD4 exposes CD4-induced epitopes on Env, rendering HIV-1 susceptible to neutralization by otherwise nonneutralizing antibodies.
感染细胞上的 CD4 下调是灵长类慢病毒的一个高度保守功能。它通过多种机制积极影响病毒复制，包括增强病毒释放和感染力、降低细胞再感染以及免受抗体依赖性细胞毒性（ADCC）的保护，ADCC 通常由需要 CD4 改变包膜（Env）构象的抗体介导。在这里，我们报告说，CD4 掺入 HIV-1 病毒粒子会影响 Env 构象，导致封闭表位暴露，这些表位被 CD4 诱导的抗体识别。这转化为这些本来非中和性抗体的中和敏感性增强，但被 HIV-1 Nef 辅助蛋白所阻止。总的来说，这些发现表明，Nef 介导的 CD4 下调的另一个功能后果是保护病毒粒子免受通常引发的 CD4 诱导抗体的中和。已经充分确立，Env-CD4 复合物在 HIV-1 感染细胞表面暴露被通常引发的 CD4 诱导抗体识别的表位，使它们容易受到 ADCC 反应的影响。在这里，我们表明 CD4 掺入对病毒粒子表面的 Env 构象有深远影响。掺入的 CD4 暴露了 Env 上的 CD4 诱导表位，使 HIV-1 容易受到本来非中和性抗体的中和。
