30% of HIV-infected subjects fail to increase their CD4 T-cell lymphocyte counts during combination antiretroviral therapy (cART) and remain both inflamed and immunodeficient. These individuals are termed “immunological non-responders.” Systemic inflammation persists in these HIV-infected patients despite the absence of detectable viremia. The reason for this persistent inflammation is unknown. We have found that that CD4 T cells in lymphoid tissues are naturally primed to mount inflammatory responses––these cells constitutively express high levels of cytoplasmic pro-IL-1b, ASC (caspase-1 adaptor protein), and NLRP3 inflammasome. The release of intracellular ATP by pyroptotic CD4 T cells may provide a second inflammatory stimulus to induce activation of caspase-1 by the NLRP3 inflammasome in surrounding uninfected CD4 T cells that are already primed. Thus, pyroptosis initiated by HIV may result in an avalanche of new rounds of pyroptosis in primed CD4 T cells by the repeated release of intracellular ATP in a virus-independent manner. Such an “auto-inflammation” scenario could generate persistent rounds of pyroptosis, chronic inflammation, and loss of CD4 T cells even when viral replication is reduced by antiretroviral therapy
Longitudinal analyses of plasma and peripheral lymphoid tissues from subject with three distinct clinical backgrounds: uninfected, infected untreated, infected treated virological suppressed.
We now show extensive caspase-1 activity and secretion of IL-18 in large areas of paracortical zones in lymph nodes freshly recovered from infected untreated patients. Interestingly, while caspase-1 activity is decreased in some subjects following treatment with antiretroviral therapy (ART), other patients exhibit persistent caspase-1 activity even when viral replication was undetectable. Moreover, in tissues where active caspase-1 was detected, we observed a significant loss of myeloid cells including resident macrophages and dendritic cells. This loss was consistent with high levels of extracellular bioactive IL-18, suggesting cell death by caspase-1-mediated pyroptosis. These findings highlight a role for pyroptosis beyond CD4 T cell death, and underscore the involvement of myeloid cells in promoting chronic inflammation and secretion of IL-18.
These preliminary findings further underscore the role of pyroptosis during R5-tropic viral infection in vivo, raising the possibility for a new class of “anti-AIDS” therapeutics.