In humans, infection with HIV-1 is associated with loss of CD4+ T cells, causing severe immunodeficiency and progression to AIDS. By contrast, some non-human primates (NHPs), which are natural hosts of the closely related SIV, are tolerant of SIV infection despite showing high levels of viraemia. Interestingly, CD4+ T cell death in humans mostly effects quiescent cells that are not productively infected (that is, they show no evidence of HIV reverse transcription or integration into the genome). Shan and colleagues now demonstrate that human CD4+ T cells die by pyroptosis in response to HIV viral entry. This is induced by activation of the CARD8 inflammasome by the viral protease, which is released from the virion during or shortly after cell entry. In activated T cells, T cell receptor (TCR) signalling seems to inhibit CARD8 activation and render the cells permissive to productive infection. Humanized mice reconstituted with CARD8-deficient T cells showed significantly lower levels of T cell depletion after HIV infection, despite high levels of viraemia. Notably, the authors identified loss-of function CARD8 mutations in NHP species that are tolerant to SIV, which may explain the non-pathogenic nature of the infection in these animals.