Cytosolic sensing of HIV by cGAS (INM2P.350)

Abstract HIV infection abrogates adaptive immunity by the depletion of CD4 T cells. However, innate immune defense mechanisms against HIV is largely unknown. Here we show that pseudotyped HIV can infect human and mouse cell lines, leading to the production of interferons and other antiviral cytokines. Activation of innate immunity by HIV requires viral cDNA synthesis but not cDNA integration. We show that retrotranscribed HIV cDNA is sensed by the cytosolic DNA sensor cGAS, which then produces the second messenger 2'3'cGAMP to activate the adaptor STING. Importantly, wild type HIV also triggers cGAMP production in human primary macrophages, underscoring the key role of cGAS in HIV sensing. Furthermore, cytosolic sensing of other retroviruses such as murine leukemia virus and simian immunodeficiency virus also depends on cGAS. These results further our understanding of immune detection of HIV and can be potentially applied in HIV vaccine and adjuvant designs.