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IFI16 DNA Sensor Is Required for Death of Lymphoid CD4 T Cells Abortively Infected with HIV

The progressive depletion of quiescent “bystander” CD4 T cells, which are nonpermissive to HIV infection, is a principal driver of the acquired immunodeficiency syndrome (AIDS). These cells undergo abortive infection characterized by the cytosolic accumulation of incomplete HIV reverse transcripts. These viral DNAs are sensed by an unidentified host sensor that triggers an innate immune response, leading to caspase-1 activation and pyroptosis. Using unbiased proteomic and targeted biochemical approaches, as well as two independent methods of lentiviral short hairpin RNA–mediated gene knockdown in primary CD4 T cells, we identify interferon-γ–inducible protein 16 (IFI16) as a host DNA sensor required for CD4 T cell death due to abortive HIV infection. These findings provide insights into a key host pathway that plays a central role in CD4 T cell depletion during disease progression to AIDS. The intracellular sensor that triggers the death of human lymphoid CD4 T cells abortively infected with HIV is identified. [Also see Perspective by Gaiha and Brass] Sensing HIV The depletion of quiescent CD4+ T cells from lymphoid organs is a major event contributing to the development of AIDS. The accumulation of incomplete HIV DNA transcripts in the cytoplasm of these cells, which do not themselves become productively infected, is somehow sensed, which triggers cell death. Monroe et al. (p. 428, published online 19 December; see the Perspective by Gaiha and Brass) now identify the host DNA sensor as interferon-γ–inducible protein 16, which senses viral DNA and activates pyroptosis, an inflammatory cell death pathway.