Alsahafi Nirmin, Richard Jonathan, Prévost Jérémie, Coutu Mathieu, Brassard Nathalie, Parsons Matthew S, Kaufmann Daniel E, Brockman Mark, Finzi Andrés
Centre de Recherche du CHUM, Montreal, QC, Canada.
Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.
J Virol. 2017 Jul 27;91(16). doi: 10.1128/JVI.00109-17. Print 2017 Aug 15.
HIV-1 Nef clones isolated from a rare subset of HIV-1-infected elite controllers (EC), with the ability to suppress viral load to undetectable levels in the absence of antiretroviral therapy, are unable to fully downregulate CD4 from the plasma membrane of CD4 T cells. Residual CD4 left at the plasma membrane allows Env-CD4 interaction, which leads to increased exposure of Env CD4-induced epitopes and increases susceptibility of infected cells to antibody-dependent cellular cytotoxicity (ADCC). ADCC is mediated largely by natural killer (NK) cells, which control their activation status through the cumulative signals received through activating and inhibitory receptors. Recently, the activating NKG2D receptor was demonstrated to positively influence ADCC responses. Since HIV-1 Nef has been reported to reduce the expression of NKG2D ligands, we evaluated the relative abilities of Nef from EC and progressors to downmodulate NKG2D ligands. Furthermore, we assessed the impact of EC and progressor Nef on the ADCC susceptibility of HIV-1-infected cells. We observed a significantly increased expression of NKG2D ligands on cells infected with viruses coding for Nef from EC. Importantly, NKG2D ligand expression levels correlated with enhanced susceptibility of HIV-1-infected cells to ADCC. The biological significance of this correlation was corroborated by the demonstration that antibody-mediated blockade of NKG2D significantly reduced ADCC of cells infected with viruses carrying Nef from EC. These results suggest the involvement of NKG2D-NKG2D ligand interactions in the enhanced susceptibility of EC HIV-1-infected cells to ADCC responses. Attenuated Nef functions have been reported in HIV-1 isolated from EC. The inability of elite controller Nef to fully remove CD4 from the surface of infected cells enhanced their susceptibility to elimination by ADCC. We now show that downregulation of NKG2D ligands by HIV-1 Nef from EC is inefficient and leaves infected cells susceptible to ADCC. These data suggest a critical role for NKG2D ligands in anti-HIV-1 ADCC responses.
从一小部分罕见的HIV-1感染精英控制者（EC）中分离出的HIV-1 Nef克隆，在没有抗逆转录病毒治疗的情况下能够将病毒载量抑制到检测不到的水平，但却无法完全下调CD4 T细胞膜表面的CD4。留在细胞膜上的残余CD4会使Env与CD4相互作用，这会导致Env CD4诱导表位的暴露增加，并增加受感染细胞对抗体依赖性细胞毒性（ADCC）的敏感性。ADCC主要由自然杀伤（NK）细胞介导，NK细胞通过激活受体和抑制受体接收的累积信号来控制其激活状态。最近，激活型NKG2D受体被证明对ADCC反应有正向影响。由于有报道称HIV-1 Nef会降低NKG2D配体的表达，我们评估了来自EC和疾病进展者的Nef下调NKG2D配体的相对能力。此外，我们评估了EC和疾病进展者的Nef对HIV-1感染细胞ADCC敏感性的影响。我们观察到，感染了编码来自EC的Nef的病毒的细胞上NKG2D配体的表达显著增加。重要的是，NKG2D配体表达水平与HIV-1感染细胞对ADCC的敏感性增强相关。抗体介导的NKG2D阻断显著降低了感染携带来自EC的Nef的病毒的细胞的ADCC，这证实了这种相关性的生物学意义。这些结果表明NKG2D-NKG2D配体相互作用参与了EC中HIV-1感染细胞对ADCC反应敏感性的增强。从EC中分离出的HIV-1已报道其Nef功能减弱。精英控制者的Nef无法完全从受感染细胞表面去除CD4，增强了它们被ADCC清除的敏感性。我们现在表明，来自EC的HIV-1 Nef对NKG2D配体的下调效率低下，使受感染细胞易受ADCC攻击。这些数据表明NKG2D配体在抗HIV-1 ADCC反应中起关键作用。
