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 TRIM5α. 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.

中文翻译：

---

破坏 HIV-1 衣壳的形成会导致病毒 DNA 的 cGAS 感应。


通过环 GMP-AMP 合酶 (cGAS) 检测病毒 DNA 是导致 I 型干扰素 (IFN) 产生的第一道防线。由于 HIV-1 复制不是 IFN 的强诱导剂，我们假设完整的衣壳以物理方式隐藏了 cGAS 中的病毒 DNA。为了测试这一点，我们通过 HIV-1 蛋白酶抑制剂处理或gag基因操作产生了有缺陷的病毒颗粒。这些病毒的 Gag 裂解存在缺陷，感染性降低，饱和 TRIM5α 的能力减弱。重要的是，与野生型 HIV-1 不同，裂解缺陷型 HIV-1 感染会在 THP-1 细胞中引发依赖于病毒 DNA 和 cGAS 的 IFN 反应。在感染裂解缺陷病毒的原代人巨噬细胞中也观察到了 IFN 反应。在存在衣壳不稳定小分子 PF-74 的情况下感染也会诱导 cGAS 依赖性 IFN 反应。这些数据证明了衣壳的保护作用，并表明衣壳和蛋白酶靶向抗病毒药物的抗病毒活性可能受益于体内先天性和适应性免疫的增强。