Effects of Brief Adjunctive Metformin Therapy in Virologically Suppressed HIV-Infected Adults on Polyfunctional HIV-Specific CD8 T cell Responses to PD-L1 Blockade.

Targeting inhibitory immune checkpoint receptor pathways has shown remarkable success in improving anti-cancer T cell responses for the elimination of tumors. Such immunotherapeutic strategies are being pursued for HIV remission. Metformin has shown favorable clinical outcomes in enhancing the efficacy of PD-1 blockade and restoring anti-tumor T cell immunity. Furthermore, monocytes are known to be a strong predictor of progression free survival in response to anti-PD-1 immunotherapy. In a single-arm clinical trial, we evaluated the immunological effects over an 8-week course of metformin therapy in seven euglycemic, virally-suppressed HIV-infected participants on combination antiretroviral therapy (cART). We assessed changes in peripheral HIV-Gag-specific T cell responses to immune checkpoint blockade (ICB) with anti-PD-L1 and anti-TIGIT monoclonal antibodies (mAbs) and changes in CD8 T cell and monocyte subsets using flow cytometry. Study participants were all male, 71% (5/7) Caucasian, with a median age of 61 years, CD4 count of 739 cells/uL and plasma HIV RNA of 1 year. Ex vivo polyfunctional HIV-Gag-specific CD8 T cell responses to anti-PD-L1 mAb significantly improved (p < 0.05) over the 8-week course of metformin therapy. Moreover, frequencies of both intermediate (CD14+CD16+) (r = 0.89, p = 0.01) and non-classical (CD14lowCD16+) (r = 0.92, p = 0.01) monocytes at entry were predictive of the magnitude of the anti-HIV CD8 T cell responses to PD-L1 blockade. Collectively, these findings highlight that 8-week course of metformin increases the polyfunctionality of CD8 T cells and that baseline monocyte subset frequencies may be a potential determinant of PD-L1 blockade efficacy. These data provide valuable information for HIV remission trials that utilize ICB strategies to enhance anti-HIV CD8 T cell immunity.