Pyroptosis Drives Both CD4 T Cell Death And Chronic Inflammation In HIV-Infected Lymphoid Tissues

Background: The progressive loss of CD4 T cells in HIV-infected individuals is the over-arching cause of AIDS. Apoptosis is the mechanism by which productively infected CD4 T-cells die. In contrast, very little is known about how “bystander” resting CD4 T cells die in lymphoid tissues. These cells are refractory to productive HIV infection yet they account >95% of the CD4 T cell losses occurring in many lymphoid tissues like tonsil and spleen. Methodology: Human lymphoid aggregated cultures (HLACs) were prepared using tonsil and spleen tissue; lymph nodes from consenting HIV-infected volunteers not on antiretroviral therapy were surgically excised and used in immuno-histological staining studies. Results: Our finding demonstrate that productive HIV infection in activated CD4 T cells from tonsil and spleen (95%) leads to by caspase-1-mediated pyroptosis, an intensely inflammatory form of programmed cell death. In the pyroptotic death pathway, cytoplasmic contents and pro-inflammatory cytokines including IL-1β, are released into the extracellular space. Surprisingly, lymphoid CD4 T-cells, but not CD8 T cells or B cells in the same tissue, are primed to mount proinflammatory death responses as reflected by high-level expression of pro-IL-1beta. These events combine to create a vicious pathogenic cycle where dying CD4 T-cells release inflammatory signals that attract more cells to become abortively infected and die by pyroptosis causing more inflammation. Cell-to-cell transmission of HIV is obligately required to elicit this pyroptotic death response-cell free virions are ineffective Pyroptosis is efficiently blocked by VX-765, a small-molecule inhibitor of caspase-1 that has been shown to be safe in humans. Analysis of lymph nodes from HIVinfected subjects confirms caspase-1 dependent pyroptotic death of bystander CD4 T cells and release of IL-1beta. Conclusions: 1. CD4 T-cell death in HIV-infected lymphoid tissues is principally controlled by caspase-1-mediated pyroptosis, an intensely inflammatory form of programmed cell death. 2. Pyroptosis provides a new and exciting nexus between CD4 T-cell death and inflammation with strong implications for HIV pathogenesis and disease progression. 3. Small-molecule inhibitors of caspase-1 could form a promising new “anti-AIDS” therapy that complements current treatment strategies by altering the detrimental host innate immune response to the virus rather than the virus itself.