Mitochondrial disturbance related to increased caspase-1 of CD4 + T cells in HIV-1 infection

In HIV-1 infection, more than 95% of CD4 T cells die of caspase-1 mediated pyroptosis. What governs the increased susceptibility of CD4 T cells to pyroptosis is poorly understood. Blood samples were obtained from 31 untreated HIV-infected patients (UNT), 29 antiretroviral therapy treated HIV-infected patients (ART), and 21 healthy control donors (HD). Plasma levels of IL-18 and IL-1β, caspase-1 expression, mitochondrial mass (MM) and mitochondrial fusion/fisson genes of CD4 T subsets were measured. A significantly higher IL-18 level in plasma and MM level of CD4 T cells were found in HIV-infected patients (UNT and ART) compared to HD, and the MM phenotype was manifested, related to increased caspase-1 expression. 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 MM was significantly correlated with an elevated level of expression of the mitochondrial fusion gene mitofusin1. An increase in MM was associated with heightened sensitivity of CD4 T cells to pyroptosis, even in early differentiated and inactivated CD4 T cells, in patients with HIV-1 infection, regardless of whether patients were on antiretroviral therapy or not. These new revelations have uncovered a previously unappreciated challenge to immune reconstitution with antiretroviral therapy.