Targeting selective miRNA in CD8+ cytotoxic T lymphocytes to enhance HIV-1 specific cytotoxic activity. undefined

miRNAs dictate relevant virus-host interactions, offering new avenues for interventions to achieve an HIV remission. We aimed to enhance HIV-specific cytotoxic responses—a hallmark of natural HIV control— by miRNA modulation in T cells. We recruited the next 12 individuals; six elite controllers and six were individuals with chronic HIV infection on long-term antiretroviral therapy. We determined HIV-specific cytotoxic responses by measuring p24 levels after CD8+ T cell co-cultures of HIV-1 transfected CD4+ T cells. miRNA signatures were defined by high-throughput sequencing. CD8+ T cells of progressors were transfected with a synthetic miRNA inhibitor. Finally, we correlated miRNA expression with changes in soluble markers of inflammation and cytotoxicity measured by Luminex. Elite controllers exhibited stronger HIV-specific cytotoxic responses than the progressors, and their CD8+T cells showed a miRNA (hsa-miR-10a-5p) significantly downregulated. When we transfected ex vivo CD8+ T cells from progressors with a synthetic miR-10a-5p inhibitor, miR-10a-5p levels decreased in 4 out of 6 progressors, correlating with an increase in HIV-specific cytotoxic responses. The effects of miR-10a-5p inhibition on HIV-specific CTL responses were modest, short-lived, and occurred before day seven after modulation. IL-4 and TNF-α levels strongly correlated with HIV-specific cytotoxic capacity. Thus, inhibition of miR-10a-5p enhanced HIV-specific CD8+ T cell capacity in progressors. Our study proves the concept that miRNA modulation is a feasible strategy to combat HIV persistence by enhancing specific cytotoxic immune responses, which will inform new approaches for achieving an antiretroviral therapy-free HIV remission.