A cGAS-mediated IFN-I response in human CD4+ T cells depends on productive infection and is conserved over HIV types and strains

HIV type 2 is known to be better controlled by our immune system than HIV-1. 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), similarly to the molecular clone HIV-1 NL4.3-GFP-I, induce a significant IFN-I response by infection of its main target, activated CD4+ T cells. However, they are unable to do so after shRNA-mediated knock-down of cGAS. In addition, HIV-1 induced IFN-I response in CD4+ T cells is dependent on productive infection and cannot be attributed to contaminating plasmid DNA present in some virus stocks. Our findings collectively showed that the cGAS-dependent innate response of CD4+ T cells to HIV infection is conserved over HIV types and critically depends on productive infection. Author Summary Our study unveils the essential role of cGAS in sensing HIV-1 and HIV-2 infections in CD4+ T cells. 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 immune response. Our findings suggest that the lower pathogenicity of HIV-2 does not correlate to superior innate immune control mediated by cGAS. By emphasizing the importance of productive infection and cGAS activity, our research advances understanding of host-pathogen relation and informs targeted strategies for combating HIV. ### Competing Interest Statement The authors have declared no competing interest.