UC Berkeley

Progression to AIDS is driven by HIV depletion of CD4 T cells. Most CD4 T cells residing in lymphoid tissues die from abortive HIV infection. During abortive infection, HIV fuses normally to quiescent cells but the elongation step of reverse transcription is very inefficient leading to cytoplasmic accumulation of short DNA transcripts. The host DNA sensor IFI16 detects these incomplete viral DNAs triggering both interferon-β expression and the assembly of inflammasomes containing caspase 1. Caspase 1 activation induces pyroptosis, a highly inflammatory form of programmed cell death. We studied whether this mechanism also promotes the death of quiescent, non-permissive CD4 T cells circulating in the blood. Here we report that blood CD4 T cells are highly resistant to pyroptosis at least in part because they lack expression of the DNA sensor, IFI16. However, blood CD4 T cells undergo HIV induced pyroptosis when co-cultured with lymphoid tissue-derived CD4 T, CD8 T, or B cells. The interactions between these co-cultured cells induce IFI16 expression likely by mimicking events occurring within lymphoid organs. These results highlight a fundamental biological difference between blood and lymphoid tissue-derived CD4 T cells and underscore AIDS as a disease of lymphatic tissue.