The mechanisms underlying depletion of CD4 T cells from multiple anatomic sites during acute HIV-1 infection are not well understood. Here we did comparative studies on cell death mechanisms in CD4 T cells from gut-associated lymphatic tissue (GALT), spleen and pelvic lymph nodes from rhesus macaques with pathogenic SIV infection.
19 animals were infected with SIVmac251 by the intravaginal route, and were necropsied on day 0, 3, 7 and 10 following infection. At necropsy, multiple tissues including colon, spleen, mesenteric lymph nodes and pelvic lymph nodes were obtained. 7 monkeys were infected with SIVmac251 by intrarectal route, and blood were collected at multiple time points from day 0 to day 245.
Peripheral blood CD4 T cells showed a modest increase of activated caspase 1 during acute SIV infection, which peaked on day 14 to the mean level of 5.5% following infection. In contrast, there was a dramatic increase of CD4 T cell pyroptosis observed on day 10 following challenge in multiple tissues, including average of 25.1% in colon, 10.6% in mesenteric lymph nodes (LN), 34.6% in spleen, and 17.6% in pelvic LNs. CD4 T cell pyroptosis showed strong negative correlation with the percentage of CD4 T cells from blood, GALT and lymphoid tissues in rhesus monkeys during early SIV infection. The upregulation of interferon-gamma inducible factor 16 (IFI16), a host DNA sensor that triggers pyroptosis, was also observed in tissue-resident CD4 T cells, and was associated with viral loads. In contrast, caspase-3-mediated apoptosis and viral cytotoxicity only accounted for a very small fraction of CD4 T cell death (< 5%), and alternative programmed cell death mechanisms, including mitochondria-induced caspase-independent cell death, necroptosis, and autophagy, did not significantly contribute to CD4 T cell depletion.
These data provide a strong in vivo evidence for a model in which caspase-1-mediated pyroptosis results in substantial CD4 T cell death in the GALT and lymphoid organs, and release of proinflammatory cytokines. These findings have important implications for our understanding of HIV-1 pathogenesis and for the development of therapeutic strategies to prevent HIV-1 immunopathogenesis.