Increased Mitochondrial Mass Related To Heightened Pyroptosis of CD4+T Cells In HIV-1 Infection

Background: In HIV-1 infection, over 90% CD4 + T cells die of caspase-1 mediated pyroptosis. What governs the increased susceptibility of CD4 + T cells to pyroptosis is poorly understood. Method: Blood samples were obtained from 31 ART-naive HIV-infected patients, 29 ART-exposed HIV-infected patients, and 21 healthy control donors. Plasma levels of IL-18 and IL-1β, activated caspase-1, mitochondrial mass (MM) and mitochondrial fusion/fisson genes of CD4 + T subsets were measured. Results: : Significantly higher IL-18 level of plasma and MM level of CD4 + T cells were found in HIV-infected patients than that in healthy controls, and the MM high phenotype manifested more sensitivity to caspase-1 mediated pyroptosis. Moreover, the increased MM was more pronounced in the early differentiated and inactivated CD4 + T cells. However, higher MM was not intrinsically linked to T cell differentiation disorder or excessive activation of the CD4 + T cells. Mechanistically, the increased mitochondrial mass was significantly correlated with an elevated expression level of the mitochondrial fusion gene-mitofusin1. Conclusion: MM increase associates with heightened sensitivity of CD4 + T cells to pyroptosis even in early differentiated and unactivated CD4 + T cells in patients with HIV-1 infection, regardless of whether the patients are on HAART or not. These new revelations uncovered a previously unappreciated challenge to immune reconstitution with antiretroviral therapy.