Increased Mitochondrial Mass Leads to Heightened Pyroptosis that Drives CD4+ T Cell Depletion in Patients with HIV-1 Infection

In HIV-1 infection, over 90% CD4+ T cells have died of caspase-1 mediated pyroptosis. What governs the increased susceptibility of CD4+ T cells to pyroptosis is poorly understood. Here, we examined the involvement of mitochondria in pyroptosis. Mitochondrial mass (MM) levels are significantly higher in CD4+ T cells from HIV-infected patients than that in healthy controls, and cells with the MMhigh phenotype manifest greater sensitivity to caspase-1 mediated pyroptosis. Moreover, the increased MM is more pronounced in the early differentiated and inactivated CD4+ T cells. However, higher MM is not intrinsically linked to T cell differentiation disorder or excessive activation of CD4+ T cells. Mechanistically, the increased MM is significantly correlated with an elevated expression of the mitochondrial fusion gene Mfn1. Additionally, MM increase in CD4+ T cells is associated with heightened sensitivity of these cells to pyroptosis in HIV-1 infected patients whom were either treated with antiretroviral drugs or not. These results reveal a previously unknown mechanism that links mitochondrial change to pyroptosis, and suggest that modulation of this interaction may help to prevent CD4+ T cell loss in HIV infection. Funding Statement: This work was funded in part by The National 13th Five-Year Plan’s Grand Program on Key Infectious Disease Control (2018ZX10302-102 to F.Z., 2018ZX10715-005 to H.Z.), the National Natural Science Foundation of China (NSFC81672000 to H.Z.), the Culture Project of Beijing Municipal Commission of Health and Family Planning (215-3-109 to L.W.), the Science and technology innovation service capacity building (1192070325 to F.Z.). Declaration of Interests: The authors have no conflicts of interest to declare. Ethics Approval Statement: Written informed consent was obtained from each subject. The local human research subject review board (RSRB) approved the study.