Killing of bystander or resting CD4+ T cells accounts for the majority of T cell loss in lymphoid organs in individuals infected with HIV and contributes to the development of AIDS. This T cell depletion was recently attributed to abortive viral infection in which HIV RNA is reverse transcribed but does not integrate into the host cell DNA. Warner Greene and his colleagues now report in two papers that such abortive infection activates sensing of the viral DNA by interferon-gamma–inducible protein 16 (IFI16) and leads to inflammatory cell death—pyroptosis—in the uninfected cells.

Doitsh et al. (doi:10.1038/nature12940, 9 December 2013) showed that death of resting CD4+ T cells owing to nonproductive HIV-1 infection did not involve apoptosis but rather pyroptosis, which is caspase-1 dependent and leads to release of the proinflammatory cytokine interleukin-1β. Inhibiting expression or activity of caspase-1 blocked T cell death in vitro.

To identify the cellular sensor of abortive infection, Monroe et al. (doi:10.1126/science.1243640, 19 December 2013) used HIV-1 DNA as bait and showed they could affinity-purify IFI16 from primary human tonsillar CD4+ T cell lysates. IFI16 bound both HIV double-stranded DNA and more weakly to single-stranded DNA. Silencing of IFI16 in CD4+ T cells in culture reduced caspase-1 activation and prevented cell death induced by abortive HIV infection.

The researchers propose that sensing of abortive infection of resting CD4+ T cells by IFI16 and consequent pyroptosis may recruit new T cell targets for infection, promoting a cycle of T cell depletion and inflammation. Blocking this cycle might prevent the loss of CD4+ T cells and progression to AIDS.