Alsahafi Nirmin, Ding Shilei, Richard Jonathan, Markle Tristan, Brassard Nathalie, Walker Bruce, Lewis George K, Kaufmann Daniel E, Brockman Mark A, Finzi Andrés
Centre de Recherche du CHUM, Université de Montréal, Montreal, Quebec, Canada Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
Centre de Recherche du CHUM, Université de Montréal, Montreal, Quebec, Canada Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Montreal, Quebec, Canada.
J Virol. 2015 Dec 30;90(6):2993-3002. doi: 10.1128/JVI.02973-15.
Impairment of Nef function, including reduced CD4 downregulation, was described in a subset of HIV-1-infected individuals that control viral replication without antiretroviral treatment (elite controllers [EC]). Elimination of HIV-1-infected cells by antibody-dependent cellular cytotoxicity (ADCC) requires the presence of envelope glycoproteins (Env) in the CD4-bound conformation, raising the possibility that accumulating CD4 at the surface of virus-infected cells in EC could interact with Env and thereby sensitize these cells to ADCC. We observed a significant increase in the exposure of Env epitopes targeted by ADCC-mediating antibodies at the surface of cells expressing Nef isolates from EC; this correlated with enhanced susceptibility to ADCC. Altogether, our results suggest that enhanced susceptibility of HIV-1-infected cells to ADCC may contribute to the EC phenotype.
Nef clones derived from elite controllers (EC) have been shown to be attenuated for CD4 downregulation; how this contributes to the nonprogressor phenotype of these infected individuals remains uncertain. Increasing evidence supports a role for HIV-specific antibody-dependent cellular cytotoxicity (ADCC) in controlling viral infection and replication. Here, we show that residual CD4 left at the surface of cells expressing Nef proteins isolated from ECs are sufficient to allow Env-CD4 interaction, leading to increased exposure of Env CD4-induced epitopes and increased susceptibility of infected cells to ADCC. Our results suggest that ADCC might be an active immune mechanism in EC that helps to maintain durable suppression of viral replication and low plasma viremia level in this rare subset of infected individuals. Therefore, targeting Nef's ability to downregulate CD4 could render HIV-1-infected cells susceptible to ADCC and thus have therapeutic utility.
在一部分未经抗逆转录病毒治疗却能控制病毒复制的HIV-1感染者（精英控制者[EC]）中，发现了Nef功能受损，包括CD4下调减少。通过抗体依赖性细胞毒性（ADCC）消除HIV-1感染细胞需要包膜糖蛋白（Env）处于CD4结合构象，这增加了一种可能性，即EC中病毒感染细胞表面积累的CD4可能与Env相互作用，从而使这些细胞对ADCC敏感。我们观察到，在表达来自EC的Nef分离株的细胞表面，ADCC介导抗体靶向的Env表位暴露显著增加；这与对ADCC的易感性增强相关。总之，我们的结果表明，HIV-1感染细胞对ADCC的易感性增强可能有助于EC表型的形成。
已证明源自精英控制者（EC）的Nef克隆在CD4下调方面减弱；这如何促成这些感染个体的非进展者表型仍不确定。越来越多的证据支持HIV特异性抗体依赖性细胞毒性（ADCC）在控制病毒感染和复制中发挥作用。在这里，我们表明，在表达从EC分离的Nef蛋白的细胞表面残留的CD4足以允许Env-CD4相互作用，导致Env CD4诱导表位的暴露增加以及感染细胞对ADCC的易感性增加。我们的结果表明，ADCC可能是EC中的一种活跃免疫机制，有助于在这一罕见的感染个体亚群中维持对病毒复制的持久抑制和低血浆病毒血症水平。因此，靶向Nef下调CD4的能力可能使HIV-1感染细胞对ADCC敏感，从而具有治疗效用。
