MRC Laboratory of Molecular Biology, Protein & Nucleic Acid Division, Cambridge, UK.
EMBO Rep. 2023 May 4;24(5):e56275. doi: 10.15252/embr.202256275. Epub 2023 Mar 27.
HIV-1 uses inositol hexakisphosphate (IP6) to build a metastable capsid capable of delivering its genome into the host nucleus. Here, we show that viruses that are unable to package IP6 lack capsid protection and are detected by innate immunity, resulting in the activation of an antiviral state that inhibits infection. Disrupting IP6 enrichment results in defective capsids that trigger cytokine and chemokine responses during infection of both primary macrophages and T-cell lines. Restoring IP6 enrichment with a single mutation rescues the ability of HIV-1 to infect cells without being detected. Using a combination of capsid mutants and CRISPR-derived knockout cell lines for RNA and DNA sensors, we show that immune sensing is dependent upon the cGAS-STING axis and independent of capsid detection. Sensing requires the synthesis of viral DNA and is prevented by reverse transcriptase inhibitors or reverse transcriptase active-site mutation. These results demonstrate that IP6 is required to build capsids that can successfully transit the cell and avoid host innate immune sensing.
HIV-1 使用肌醇六磷酸 (IP6) 构建一种亚稳态衣壳，使其基因组能够进入宿主细胞核。在这里，我们表明，无法包装 IP6 的病毒缺乏衣壳保护，会被先天免疫检测到，从而激活抗病毒状态，抑制感染。破坏 IP6 的富集会导致缺陷衣壳，在原发性巨噬细胞和 T 细胞系感染过程中触发细胞因子和趋化因子反应。用单个突变恢复 IP6 的富集可以挽救 HIV-1 感染细胞而不被检测到的能力。使用衣壳突变体和 CRISPR 衍生的 RNA 和 DNA 传感器敲除细胞系的组合，我们表明免疫感应依赖于 cGAS-STING 轴，而不依赖于衣壳检测。这种感应需要病毒 DNA 的合成，并且可以被逆转录酶抑制剂或逆转录酶活性位点突变所阻止。这些结果表明，IP6 是构建能够成功穿越细胞并逃避宿主先天免疫感应的衣壳所必需的。
