Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany.
Institute of Molecular Bacteriology, TWINCORE, 30625 Hanover, Germany; Department of Molecular Bacteriology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
Cell Host Microbe. 2016 Oct 12;20(4):443-457. doi: 10.1016/j.chom.2016.09.003.
Upon sensing cytoplasmic retroviral DNA in infected cells, cyclic GMP-AMP (cGAMP) synthase (cGAS) produces the cyclic dinucleotide cGAMP, which activates STING to trigger a type I interferon (IFN) response. We find that membrane fusion-inducing contact between donor cells expressing the HIV envelope (Env) and primary macrophages endogenously expressing the HIV receptor CD4 and coreceptor enable intercellular transfer of cGAMP. This cGAMP exchange results in STING-dependent antiviral IFN responses in target macrophages and protection from HIV infection. Furthermore, under conditions allowing cell-to-cell transmission of HIV-1, infected primary T cells, but not cell-free virions, deliver cGAMP to autologous macrophages through HIV-1 Env and CD4/coreceptor-mediated membrane fusion sites and induce a STING-dependent, but cGAS-independent, IFN response in target cells. Collectively, these findings identify an infection-specific mode of horizontal transfer of cGAMP between primary immune cells that may boost antiviral responses, particularly in infected tissues in which cell-to-cell transmission of virions exceeds cell-free infection.
当感染细胞检测到细胞质逆转录病毒 DNA 时，环鸟苷酸-腺苷酸 (cGAMP) 合酶 (cGAS) 会产生环二核苷酸 cGAMP，它会激活 STING 以触发 I 型干扰素 (IFN) 反应。我们发现，表达 HIV 包膜 (Env) 的供体细胞与内源性表达 HIV 受体 CD4 和共受体的原代巨噬细胞之间的膜融合诱导接触，使 cGAMP 在细胞间转移。这种 cGAMP 交换导致靶巨噬细胞中依赖 STING 的抗病毒 IFN 反应，并防止 HIV 感染。此外，在允许 HIV-1 细胞间传播的条件下，感染的原代 T 细胞而非无细胞病毒颗粒通过 HIV-1 Env 和 CD4/共受体介导的膜融合位点将 cGAMP 传递给自体巨噬细胞，并在靶细胞中诱导依赖 STING 但不依赖 cGAS 的 IFN 反应。总之，这些发现确定了原发性免疫细胞之间 cGAMP 的一种感染特异性水平转移模式，它可能增强抗病毒反应，特别是在病毒颗粒细胞间传播超过无细胞感染的感染组织中。
