Abstract
BACKGROUND: Virus-specific CD8(+) T cells play a major role in the natural control of HIV infection, linked to memory-like features such as high survival capacity and polyfunctionality. However, virus-specific CD8(+) T cells from HIV non-controllers exhibit an effector-like and exhausted profile, with limited antiviral potential. Metabolic reprogramming of cells from non-controllers could reinvigorate their functional capacities. Considering the implication of the cholesterol pathway in the induction of T cell exhaustion, here we evaluated the impact of rosuvastatin, an inhibitor of cholesterol synthesis, on the functionality and memory profile of HIV-specific CD8(+) T cells from people on antiretroviral treatment. METHODS: We analysed samples from 10 individuals with HIV-1 on ART who participated in the IMEA 043-CESAR trial and received rosuvastatin for 12 weeks. We explored whether rosuvastatin treatment was accompanied by changes in the memory potential of CD8(+) T cells. We evaluated the phenotype and functionality of total and HIV-specific CD8(+) T cells before, during, and after treatment with rosuvastatin. A mixed effects model was used for repeated measures and corrected for multiple comparisons. FINDINGS: Total and HIV-specific CD8(+) T cell survival and functionality were enhanced in individuals who received a 12-week course of rosuvastatin, with a consistent increase in polyfunctional IFN-γ(+) TNF-α(+) cells. The superior CD8(+) T cell functionality after rosuvastatin treatment was associated with intrinsic metabolic changes, including the decrease of fatty acid uptake, as well as a reduction in effector/exhaustion markers. Changes in the characteristics of CD8(+) T cells coincided with the duration of rosuvastatin administration, and most effects waned after the cessation of the treatment. INTERPRETATION: CD8(+) T cell metabolic reprogramming by targeting the cholesterol pathway, combined with other available immunotherapies, might represent a promising strategy in the search for the cure of HIV or other chronic viral infections. FUNDING: The CESAR trial was sponsored by IMEA. This work was supported by the NIH (grants UM1AI164562 and R01DK131476).