Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.
Ghent University Hospital, Ghent, Belgium.
J Virol. 2024 Oct 22;98(10):e0087724. doi: 10.1128/jvi.00877-24. Epub 2024 Sep 13.
Human immunodeficiency virus (HIV) type 2 is known to be less pathogenic than HIV-1, possibly due to more effective immune control mechanisms. The mechanism of innate sensing of HIV-2 by T cells is at present unclear. In this study, we show that several primary isolates of HIV-2 (CBL20 and CI85) and HIV-1 (A8 and D2), similar to the molecular clone HIV-1 NL4.3-GFP-I, induce a significant type I interferon response in its main target, activated CD4+ T cells. However, they are unable to do so after shRNA-mediated knock-down of cGAS. In addition, both HIV-1- and HIV-2-induced type I interferon response in CD4+ T cells was dependent on productive infection and integration, as the presence of RT or integrase inhibitor dramatically suppressed the sensing. Our findings collectively showed that the cGAS-dependent type I interferon response of CD4+ T cells to HIV infection is conserved over HIV types and critically depends on productive infection.IMPORTANCEBy unveiling the role of cGAS in sensing Human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) across CD4+ T cells and highlighting its broader relevance that might be mirrored in other cell types, our research provides insights into the uniform mechanism of innate immune activation by different HIV isolates. By demonstrating the necessity of productive infection, we highlight the robust and specific nature of the observed cGAS-mediated innate response, dispelling concerns about contaminating plasmids triggering an immune response. Our preliminary data suggest that the lower pathogenicity of HIV-2 may not be directly correlated to superior innate immune control mediated by cGAS.
人类免疫缺陷病毒（HIV）2 型被认为比 HIV-1 型的致病性低，这可能是由于更有效的免疫控制机制。目前，T 细胞对 HIV-2 的先天感应机制尚不清楚。在这项研究中，我们表明，几种 HIV-2（CBL20 和 CI85）和 HIV-1（A8 和 D2）的原始分离株与分子克隆 HIV-1 NL4.3-GFP-I 相似，可在其主要靶标激活的 CD4+T 细胞中诱导显著的 I 型干扰素反应。然而，在用 shRNA 介导的 cGAS 敲低后，它们无法做到这一点。此外，HIV-1 和 HIV-2 在 CD4+T 细胞中诱导的 I 型干扰素反应均依赖于有性感染和整合，因为 RT 或整合酶抑制剂的存在可显著抑制感应。我们的研究结果表明，CD4+T 细胞对 HIV 感染的 cGAS 依赖性 I 型干扰素反应在 HIV 类型之间是保守的，并且严重依赖于有性感染。
重要性
通过揭示 cGAS 在识别 CD4+T 细胞中的 HIV 1 型和 2 型（HIV-1 和 HIV-2）中的作用，并强调其在其他细胞类型中可能具有更广泛的相关性，我们的研究为不同 HIV 分离株固有免疫激活的统一机制提供了新的见解。通过证明有性感染的必要性，我们突出了观察到的 cGAS 介导的先天反应的强大和特异性，消除了对污染质粒引发免疫反应的担忧。我们的初步数据表明，HIV-2 的低致病性可能与 cGAS 介导的先天免疫控制的优越性没有直接相关性。
