Background: Depletion of CD4 T cells and development of chronic inflammation are signature processes in HIV pathogenesis that propel disease progression. Due to endogenous SAMHD1 restriction activity in quiescent lymphoid CD4 T cells, the viral chain elongation phase of reverse transcription is attenuated, giving rise to incomplete cytosolic DNA transcripts. CD4 T-cell death is triggered after sensing of these cytosolic DNA intermediates by interferon gamma Inducible protein 16 (IFI16). Death occurs following caspase-1 activation in inflammasomes and the induction of pyroptosis, a highly inflammatory form of programmed cell death. These findings mechanistically connect CD4 T-cell death and chronic inflammation––the two signature pathogenic processes of active HIV infection.
Methods: Human lymphoid aggregated cultures (HLACs) prepared using tonsil and spleen, and lymph node biopsies from consenting HIV-infected volunteers were used.
Results: We now show that SAMHD1 restriction activity influences how CD4 T cells die. Degradation of SAMHD1 by Vpx encoded by HIV-2 thwarts abortive infection in resting, non-permissive lymphoid CD4 T cells redirecting the cell death pathway away from caspase-1-mediated pyroptotic pathway (inflammatory) toward caspase-3-mediated apoptotic pathway (noninflammatory). SAMHD1 effectively suppresses caspase-1 activation and pyroptosis when infection occurs with cell-free virions. However, in the context of cell-to-cell transmission, which is 100-1,000-fold more efficient, SAMHD1 restriction is only partially effective resulting in the accumulation cytoplasmic viral DNA. This DNA is sensed by IFI16 resulting in caspase-1 activation and triggering of the pyroptotic death pathway. The action of other cellular factors like TREX1 and SLX4 (single and double strand DNA nucleases) may require further increase in the levels the cytosolic DNA needed to trigger pyroptosis.
Conclusions: 1. The Vpx protein thwarts inflammatory pyroptosis following HIV-2 infection by degrading SAMHD1 thereby avoiding abortive infection and sensing of cytosolic viral DNA.
2. SAMHD1 is a bifunctional host factor capably restricting infection of resting CD4 T cells by cell-free HIV virions but functioning as a pro-pathogenic factor when resting CD4 T cells are infected by HIV-1 by the cell-to-cell route.