One of characteristics of chronic HIV-1 infection in patients is a progressive loss of CD4 + T cells, which consequently disrupts immune responses. A better understanding of the processes that mediate such depletion could pave the way for the development of more targeted anti-HIV therapies.In a recent study, Zhang et al.[1] demonstrated in viremic HIV-1–infected patients that a specific type of cell death—pyroptosis—plays a pivotal role in CD4 + T cell loss. Specifically, using peripheral blood samples from viremic patients as well as healthy controls, they used flow cytometry to monitor activation of both caspase-1 and caspase-3 in T cells, which are markers of pyroptosis and apoptosis, respectively. They found that pyroptotic and apoptotic CD4 + T cells constituted distinct populations with different phenotypes. In addition they observed that levels of both pyroptosis and apoptosis in CD4 + T cells were significantly elevated during HIV-1 infection, and were decreased following antiretroviral therapy.PixabayCritically, they also showed that pyroptosis was the more dominant pathway. Whilst current treatments can reduce the occurrence of pyroptosis, they cannot fully eradicate it. Zhang et al.[1] also found that the mechanisms underlying depletion were different for pyroptotic and apoptotic CD4 + T cells. In the case of pyroptotic cells, they found that caspase 1activation was closely correlated with expression of inflammatory markers, such as cytokines, and was dependent on NLRP3 inflammasome activation, which plays a key role in innate immunity. In the case of the apoptosis however, caspase-3 activation in CD4 + T cells was more closely related to the T cell activation status.Taken together, this study reveals that NLRP3 inflammasome-dependent pyroptosis plays a key role in CD4 + T cell loss in patients with HIV-1 infections. This could open up new avenues in the development of anti-HIV-1 therapies that target components of the pyroptosis pathway.