The pathway causing CD4 T-cell death in HIV-infected hosts remains poorly understood. Apoptosis has been proposed as the key mechanism for CD4 T-cell loss. We now show that caspase-3-mediated apoptosis accounts for the death of only a small fraction of productively infected cells. The remaining >95% of quiescent lymphoid CD4 T-cells die by caspase-1-mediated pyroptosis triggered by abortive viral infection. Pyroptosis corresponds to an intensely inflammatory form of programmed cell death where cytoplasmic contents and pro-inflammatory cytokines including IL-1β, are released. This death pathway thus links the two signature events in HIV infection––CD4 T-cell depletion and chronic inflammation––and creates a vicious pathogenic cycle where dying CD4 T-cells release inflammatory signals that attract more cells to die. This cycle can be broken by caspase-1 inhibitors shown to be safe in humans, raising the possibility of a new class of “anti-AIDS” therapeutics targeting the host rather than the virus.

The progressive depletion of quiescent “bystander” CD4 T-cells, which are non-permissive 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 shRNA-mediated gene knockdown in primary CD4 T-cells, we identify Interferon gamma 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.

During apoptosis, dying cells are swiftly removed by phagocytes. How apoptotic cells are recognized by phagocytes is not fully understood. Here we report the identification and characterization of the C. elegans ttr-52 gene, which is required for efficient cell corpse engulfment and encodes a transthyretin-like protein. The TTR-52 protein is expressed in and secreted from C. elegans endoderm and clusters around apoptotic cells. Genetic analysis indicates that TTR-52 acts in the cell corpse engulfment pathway mediated by CED-1, CED-6, and CED-7 and affects clustering of the phagocyte receptor CED-1 around apoptotic cells. Interestingly, TTR-52 recognizes surface exposed phosphatidylserine (PS) in vivo and binds to both PS and the extracellular domain of CED-1 in vitro. Therefore, TTR-52 is the first bridging molecule identified in C. elegans that mediates recognition of apoptotic cells by cross-linking the PS “eat me” signal with the phagocyte receptor CED-1.

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