Foster Toshana L, Wilson Harry, Iyer Shilpa S, Coss Karen, Doores Katie, Smith Sarah, Kellam Paul, Finzi Andrés, Borrow Persephone, Hahn Beatrice H, Neil Stuart J D
Department of Infectious Diseases, King's College London Faculty of Life Sciences and Medicine, Guy's Hospital, London SE1 9RT, UK.
Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell Host Microbe. 2016 Oct 12;20(4):429-442. doi: 10.1016/j.chom.2016.08.006. Epub 2016 Sep 15.
Interferon-induced transmembrane proteins (IFITMs) restrict the entry of diverse enveloped viruses through incompletely understood mechanisms. While IFITMs are reported to inhibit HIV-1, their in vivo relevance is unclear. We show that IFITM sensitivity of HIV-1 strains is determined by the co-receptor usage of the viral envelope glycoproteins as well as IFITM subcellular localization within the target cell. Importantly, we find that transmitted founder HIV-1, which establishes de novo infections, is uniquely resistant to the antiviral activity of IFITMs. However, viral sensitivity to IFITMs, particularly IFITM2 and IFITM3, increases over the first 6 months of infection, primarily as a result of neutralizing antibody escape mutations. Additionally, the ability to evade IFITM restriction contributes to the different interferon sensitivities of transmitted founder and chronic viruses. Together, these data indicate that IFITMs constitute an important barrier to HIV-1 transmission and that escape from adaptive immune responses exposes the virus to antiviral restriction.
干扰素诱导跨膜蛋白（IFITMs）通过尚未完全明确的机制限制多种包膜病毒的进入。虽然有报道称IFITMs可抑制HIV-1，但其在体内的相关性尚不清楚。我们发现，HIV-1毒株对IFITMs的敏感性由病毒包膜糖蛋白的共受体使用情况以及IFITMs在靶细胞内的亚细胞定位决定。重要的是，我们发现能够引发初始感染的传播奠基型HIV-1对IFITMs的抗病毒活性具有独特的抗性。然而，在感染的最初6个月内，病毒对IFITMs（尤其是IFITM2和IFITM3）的敏感性会增加，这主要是中和抗体逃逸突变的结果。此外，逃避IFITM限制的能力导致了传播奠基型病毒和慢性病毒对干扰素敏感性的差异。这些数据共同表明，IFITMs构成了HIV-1传播的重要障碍，而逃避适应性免疫反应会使病毒暴露于抗病毒限制之下。
