Blood-Derived CD4 T Cells Naturally Resist Pyroptosis during Abortive HIV-1 Infection

The progressive loss of CD4 T cells lies at the heart of HIV/AIDS. HIV infects and kills activated CD4 T cells by apoptosis, but these permissive cells are too few in number to explain the massive CD4 T cell losses observed in untreated, HIV-infected people.  We recently reported that most CD4 T cells residing in lymphoid tissues correspond to bystander cells that die by abortive HIV infection involving pyroptosis, a highly inflammatory form of programmed cell death. For pyroptosis to occur, the virus must be transmitted to quiescent CD4 T cells through virological synapses (cell-to-cell transmission is required)(Galloway et al., 2015), but in these resting cells, the viral life cycle is arrested during the elongation step of reverse transcription.  Consequently, incomplete HIV DNA transcripts accumulate in the cytosol.  These viral DNAs are detected by the IFI16 DNA sensor (Monroe et al., 2014), which can recognize both single and double stranded DNA targets. Detection of these transcripts triggers an innate immune response involving the assembly of the IFI16 inflammasome, induction of type I interferon and pyroptosis involving caspase-1 activation.

Pyroptosis of spleen, tonsil, and gut-associated-lymphoid tissue-derived CD4 T cells infected with CXCR4 or CCR5 tropic HIV has been shown (Doitsh et al., 2010; Doitsh et al., 2014; Steele et al., 2014) but the susceptibility of blood-derived CD4 T cells to this mechanism of depletion was unknown. We now report that CD4 T cells are resistant to this death pathway while circulating in the blood stream. This resistance is, at least in part, due to a deeper resting state for these cells resulting in the accumulation of less HIV DNA transcripts and lower expression of the DNA sensor, IFI16. Surprisingly, co-culture allowing direct contact with lymphoid tissue-derived CD4 T, CD8 T, or B cells renders blood-derived CD4 T cells sensitive to HIV mediated pyroptosis. Reverse transcription improves and IFI16 levels rise. Continuous interaction between the tissue and blood cells are required to maintain the sensitivity to pyroptosis. The natural resistance of blood cells to HIV-elicited pyroptosis extends beyond virally infected cells––exposure of these cells to nigericin, an activator of the NLRP3 inflammasome also does not result in pyroptosis(Munoz-Arias et al., 2015)

Our work highlights how the tissue micro-environment shapes the response of CD4 T cells to HIV infection. Indeed, if we had begun our studies with blood instead of lymphoid tissue-derived CD4 T cells, we would have not detected the pyroptotic death pathway, which appears to account for depletion of a significant fraction of CD4 T cells during HIV infection. Further studies are now underway to identify the lymphoid tissue factor(s) involved in sensitizing CD4 T cells to HIV-mediated pyroptosis. Inhibition of the interplay of these factors could lead to host directed therapy that would prevent CD4 T cell death but it will be important to exclude detrimental effects of this treatment on the normal immune response.