Abstract
SummarySAMHD1 is a restriction factor for HIV-1 infection. SAMHD1 mutations cause the autoinflammatory Aicardi-Goutières syndrome that is characterized by chronic type I interferon (IFN) secretion. We show that the spontaneous IFN response in SAMHD1-deficient cells and mice requires the cGAS/STING cytosolic DNA-sensing pathway. We provide genetic evidence that cell-autonomous control of lentivirus infection in myeloid cells by SAMHD1 limits virus-induced production of IFNs and the induction of co-stimulatory markers. This program of myeloid cell activation required reverse transcription, cGAS and STING, and signaling through the IFN receptor. Furthermore, SAMHD1 reduced the induction of virus-specific cytotoxic T cells in vivo. Therefore, virus restriction by SAMHD1 limits the magnitude of IFN and T cell responses. This demonstrates a competition between cell-autonomous virus control and subsequent innate and adaptive immune responses, a concept with important implications for the treatment of infection.
Highlights
Virus infection in mammalian hosts is controlled by a variety of mechanisms operating at different levels
The Spontaneous IFN Response in Samhd1À/À Cells and Mice Requires cGAS and STING Aicardi-Goutieres syndrome (AGS) is a prototypical interferonopathy, a group of diseases characterized by chronic and pathologic IFN production (Crow and Manel, 2015)
Consistent with previous observations, Samhd1À/À bone marrow-derived macrophages (BMDMs) expressed higher mRNA levels of the interferon-stimulated genes (ISGs) Ifi44, Ifit1, and Ifit2 compared to wild-type cells (Figure 1A)
Summary
Virus infection in mammalian hosts is controlled by a variety of mechanisms operating at different levels These include cellintrinsic restriction systems, innate immune sensors that signal for the induction of an antiviral state, and cellular and adaptive immune responses. How these different branches of the antiviral response work together is important for successful immunity. Restriction factors have been studied in particular detail for HIV-1 and include APOBEC3G, TRIM5a, tetherin, and Mx2 (Rehwinkel, 2014; Simon et al, 2015). Additional mechanisms by which SAMHD1 might restrict infection have been proposed and include degradation and/or binding of viral nucleic acids (Ballana and Este , 2015)
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