Center for Infectious Disease Research, Seattle, WA 98109, USA.
Center for Infectious Disease Research, Seattle, WA 98109, USA.
Cell Host Microbe. 2018 Mar 14;23(3):366-381.e9. doi: 10.1016/j.chom.2018.01.012.
Myeloid dendritic cells (DCs) have the innate capacity to sense pathogens and orchestrate immune responses. However, DCs do not mount efficient immune responses to HIV-1, primarily due to restriction of virus reverse transcription, which prevents accumulation of viral cDNA and limits its detection through the cGAS-STING pathway. By allowing reverse transcription to proceed, we find that DCs detect HIV-1 in distinct phases, before and after virus integration. Blocking integration suppresses, but does not abolish, activation of the transcription factor IRF3, downstream interferon (IFN) responses, and DC maturation. Consistent with two stages of detection, HIV-1 "primes" chromatin accessibility of innate immune genes before and after integration. Once primed, robust IFN responses can be unmasked by agonists of the innate adaptor protein, MyD88, through a process that requires cGAS, STING, IRF3, and nuclear factor κB. Thus, HIV-1 replication increases material available for sensing, and discrete inflammatory inputs tune cGAS signaling to drive DC maturation.
髓样树突状细胞（DCs）具有先天感知病原体并协调免疫反应的能力。然而，DC 并不能对 HIV-1 产生有效的免疫反应，主要是因为病毒逆转录受到限制，这阻止了病毒 cDNA 的积累，并通过 cGAS-STING 途径限制了其检测。通过允许逆转录进行，我们发现 DC 在病毒整合之前和之后的不同阶段检测到 HIV-1。阻断整合会抑制，但不会完全抑制转录因子 IRF3 的激活、下游干扰素（IFN）反应和 DC 成熟。与两个检测阶段一致，HIV-1 在整合前后“启动”先天免疫基因的染色质可及性。一旦被启动，通过一种需要 cGAS、STING、IRF3 和核因子 κB 的过程，先天衔接蛋白 MyD88 的激动剂可以揭示强大的 IFN 反应。因此，HIV-1 复制增加了可用于感知的物质，而离散的炎症输入则调节 cGAS 信号以驱动 DC 成熟。
