Disrupting HIV-1 capsid formation causes cGAS sensing of viral DNA

Detection of viral DNA by cyclic GMP-AMP synthase (cGAS) is a first line of defence leading to the production of type-I interferon (IFN). As HIV-1 replication is not a strong inducer of IFN we hypothesised that an intact capsid physically cloaks viral DNA from cGAS. To test this we generated defective viral particles by treatment with HIV-1 protease inhibitors or by genetic manipulation of gag. These viruses had defective Gag cleavage, reduced infectivity and diminished capacity to saturate TRIM5?. Importantly, unlike wild-type HIV-1, infection with cleavage defective HIV-1 triggered an IFN response in THP-1 cells that was dependent on viral DNA and cGAS. An IFN response was also observed in primary human macrophages infected with cleavage defective viruses. Infection in the presence of the capsid destabilising small molecule PF-74 also induced a cGAS-dependent IFN response. These data demonstrate a protective role for capsid and suggest that antiviral activity of capsid- and protease-targeting antivirals may benefit from enhanced innate and adaptive immunity in vivo.

环鸟苷酸-腺苷酸合成酶（cGAS）识别病毒DNA是触发I型干扰素（IFN）产生的第一道免疫防线。由于人类免疫缺陷病毒1型（HIV-1）的复制并非I型干扰素的强诱导剂，我们推测完整的病毒衣壳可通过物理遮蔽病毒DNA，使其免于被cGAS识别。为验证这一假说，我们通过HIV-1蛋白酶抑制剂处理或对gag基因进行遗传操作，制备了缺陷型病毒颗粒。这类病毒存在Gag蛋白切割缺陷、感染性降低，且饱和TRIM5的能力减弱。值得注意的是，与野生型HIV-1不同，感染切割缺陷型HIV-1可在THP-1细胞中触发依赖于病毒DNA与cGAS的干扰素应答；在感染切割缺陷型病毒的原代人巨噬细胞中，同样观测到此类应答。使用衣壳稳定性破坏小分子PF-74的感染实验，也诱导了依赖cGAS的干扰素应答。上述数据证实了病毒衣壳的免疫保护作用，并提示靶向衣壳与蛋白酶的抗病毒药物的抗病毒活性，或可通过增强体内固有免疫与适应性免疫而获得提升。