Pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Researchers found that in HIV-1 infected individuals, CD4 T-cell death is primarily caused by pyroptosis, a highly inflammatory form of programmed cell death triggered by abortive viral infection. While apoptosis has been proposed as the main mechanism for CD4 T-cell loss, the study shows that caspase-3-mediated apoptosis accounts for only a small fraction of productively infected cells. The majority of CD4 T-cells, which are quiescent and not productively infected, die via caspase-1-mediated pyroptosis. This process involves the release of inflammatory cytokines, including IL-1β, and contributes to chronic inflammation and a vicious cycle of CD4 T-cell death and inflammation. Caspase-1 inhibitors, which are safe in humans, can break this cycle, suggesting a new class of "anti-AIDS" therapeutics targeting the host rather than the virus. The study used an ex vivo human lymphoid aggregate culture (HLAC) system to investigate CD4 T-cell death during HIV infection. Infection of these cultures with HIV-1 leads to extensive loss of CD4 T cells, with over 95% of dying cells being abortively infected. The HIV life cycle is disrupted during reverse transcription, leading to incomplete viral DNA transcripts. This triggers an innate immune response, resulting in caspase-3 and caspase-1 activation. Caspase-3 activation leads to apoptosis without inflammation, while caspase-1 activation triggers pyroptosis, a highly inflammatory form of cell death. The study found that caspase-1 is activated in lymphoid CD4 T cells following abortive HIV infection, leading to pyroptosis and the release of bioactive IL-1β. The study also showed that healthy lymphoid CD4 T cells express pro-IL-1β, which is processed and released by caspase-1 activation. This process is particularly prominent in CCR5-expressing CD4 T cells, which are more permissive for productive HIV infection. The study further demonstrated that caspase-1 inhibitors, such as VX-765, can prevent CD4 T-cell death and inflammation in HIV-infected tissues. These findings suggest that targeting caspase-1 could be a promising therapeutic approach for HIV infection.Pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Researchers found that in HIV-1 infected individuals, CD4 T-cell death is primarily caused by pyroptosis, a highly inflammatory form of programmed cell death triggered by abortive viral infection. While apoptosis has been proposed as the main mechanism for CD4 T-cell loss, the study shows that caspase-3-mediated apoptosis accounts for only a small fraction of productively infected cells. The majority of CD4 T-cells, which are quiescent and not productively infected, die via caspase-1-mediated pyroptosis. This process involves the release of inflammatory cytokines, including IL-1β, and contributes to chronic inflammation and a vicious cycle of CD4 T-cell death and inflammation. Caspase-1 inhibitors, which are safe in humans, can break this cycle, suggesting a new class of "anti-AIDS" therapeutics targeting the host rather than the virus. The study used an ex vivo human lymphoid aggregate culture (HLAC) system to investigate CD4 T-cell death during HIV infection. Infection of these cultures with HIV-1 leads to extensive loss of CD4 T cells, with over 95% of dying cells being abortively infected. The HIV life cycle is disrupted during reverse transcription, leading to incomplete viral DNA transcripts. This triggers an innate immune response, resulting in caspase-3 and caspase-1 activation. Caspase-3 activation leads to apoptosis without inflammation, while caspase-1 activation triggers pyroptosis, a highly inflammatory form of cell death. The study found that caspase-1 is activated in lymphoid CD4 T cells following abortive HIV infection, leading to pyroptosis and the release of bioactive IL-1β. The study also showed that healthy lymphoid CD4 T cells express pro-IL-1β, which is processed and released by caspase-1 activation. This process is particularly prominent in CCR5-expressing CD4 T cells, which are more permissive for productive HIV infection. The study further demonstrated that caspase-1 inhibitors, such as VX-765, can prevent CD4 T-cell death and inflammation in HIV-infected tissues. These findings suggest that targeting caspase-1 could be a promising therapeutic approach for HIV infection.