Institute of Molecular Virology - Ulm University Medical Center, Meyerhofstraße 1, 89081 Ulm, Germany.
German Primate Center, Kellnerweg 4, 37077 Göttingen, Germany.
Cell Rep. 2020 Feb 18;30(7):2261-2274.e7. doi: 10.1016/j.celrep.2020.01.069.
The inability of Nef to downmodulate the CD3-T cell receptor (TCR) complex distinguishes HIV-1 from other primate lentiviruses and may contribute to its high virulence. However, the role of this Nef function in virus-mediated immune activation and pathogenicity remains speculative. Here, we selectively disrupted this Nef activity in SIV and analyzed the consequences for the virological, immunological, and clinical outcome of infection in rhesus macaques. The inability to downmodulate CD3-TCR does not impair viral replication during acute infection but is associated with increased immune activation and antiviral gene expression. Subsequent early reversion in three of six animals suggests strong selective pressure for this Nef function and is associated with high viral loads and progression to simian AIDS. In the absence of reversions, however, viral replication and the clinical course of infection are attenuated. Thus, Nef-mediated downmodulation of CD3 dampens the inflammatory response to simian immunodeficiency virus (SIV) infection and seems critical for efficient viral immune evasion.
Nef 无法下调 CD3-T 细胞受体 (TCR) 复合物的能力将 HIV-1 与其他灵长类慢病毒区分开来，并且可能导致其高毒性。然而，这种 Nef 功能在病毒介导的免疫激活和致病性中的作用仍然是推测性的。在这里，我们在 SIV 中选择性地破坏了这种 Nef 活性，并分析了对恒河猴感染的病毒学、免疫学和临床结果的影响。下调 CD3-TCR 的能力不会损害急性感染期间的病毒复制，但与免疫激活和抗病毒基因表达增加有关。随后在六只动物中的三只中出现的早期回复表明这种 Nef 功能受到强烈的选择压力，并且与高病毒载量和向猿猴艾滋病的进展有关。然而，在没有回复的情况下，病毒复制和感染的临床过程减弱。因此，Nef 介导的 CD3 下调抑制了对猿猴免疫缺陷病毒 (SIV) 感染的炎症反应，并且似乎对于有效的病毒免疫逃避至关重要。
