Laboratory of Immunoinfectivology, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy.
J Virol. 2012 Apr;86(8):4496-504. doi: 10.1128/JVI.05788-11. Epub 2012 Feb 1.
The human immunodeficiency virus type 1 (HIV-1) evades the immune responses of natural killer (NK) cells through mechanisms that have been partially deciphered. Here we show that in HIV-1-infected T lymphocytes, the early viral Nef protein downmodulates PVR (CD155, Necl-5), a ligand for the activating receptor DNAM-1 (CD226) expressed by all NK cells, CD8(+) T cells, and other cell types. This novel Nef activity is conserved by Nef proteins of laboratory HIV-1 strains (NL4-3, SF2) and of a patient-derived virus, but it is not maintained by HIV-2. Nef uses the same motifs to downregulate PVR and HLA-I molecules, likely by the same mechanisms. Indeed, as previously demonstrated for HLA-I, Nef reduces the total amounts of cell-associated PVR. Optimal downregulation of cell surface PVR by Nef also requires the presence of the late viral factor Vpu. In line with PVR reduction, the NK cell-mediated lysis of T cells infected by a wild-type but not Nef-deficient virus is virtually abrogated upon blocking of both DNAM-1 and another activating receptor, NKG2D, previously shown to mediate killing of HIV-infected cells. Together, these data demonstrate that the PVR downmodulation by Nef and Vpu is a strategy evolved by HIV-1 to prevent NK cell-mediated lysis of infected cells. The PVR downregulation reported here has the potential to affect the immune responses of other DNAM-1-positive cells besides NK cells and to alter multiple PVR-mediated cellular processes, such as adhesion and migration, and may thus greatly influence HIV-1 pathogenesis.
人类免疫缺陷病毒 1 型（HIV-1）通过部分阐明的机制逃避自然杀伤（NK）细胞的免疫反应。在这里，我们表明在 HIV-1 感染的 T 淋巴细胞中，早期病毒 Nef 蛋白下调 PVR（CD155，Necl-5），这是所有 NK 细胞、CD8+T 细胞和其他细胞类型表达的激活受体 DNAM-1（CD226）的配体。这种新型 Nef 活性被实验室 HIV-1 株（NL4-3、SF2）和源自患者的病毒的 Nef 蛋白保守，但 HIV-2 不维持。Nef 使用相同的基序下调 PVR 和 HLA-I 分子，可能通过相同的机制。事实上，正如先前针对 HLA-I 所证明的，Nef 减少了细胞相关 PVR 的总量。Nef 对细胞表面 PVR 的最佳下调也需要存在晚期病毒因子 Vpu。与 PVR 减少一致，当阻断 DNAM-1 和另一种激活受体 NKG2D 时，野生型而非 Nef 缺陷型病毒感染的 T 细胞的 NK 细胞介导的裂解几乎被消除，先前显示这两种受体介导对感染 HIV 的细胞的杀伤。总之，这些数据表明 Nef 和 Vpu 下调 PVR 是 HIV-1 进化而来的一种策略，以防止 NK 细胞介导的感染细胞裂解。这里报道的 PVR 下调有可能影响除 NK 细胞以外的其他表达 DNAM-1 的细胞的免疫反应，并改变多种 PVR 介导的细胞过程，如粘附和迁移，并且可能极大地影响 HIV-1 发病机制。
