Short Communication: Metformin Reduces CD4 T Cell Exhaustion in HIV-Infected Adults on Suppressive Antiretroviral Therapy

Abstract

Increased negative immune checkpoint receptors (NCR) on T cells are linked to T cell exhaustion, dysfunctional effector responses, and HIV viral persistence. Metformin, an oral hypoglycemic agent used for diabetes, may have previously unrecognized beneficial immunologic effects. Using cryopreserved blood from a 24-week pilot study involving 12 virally suppressed HIV-infected individuals randomized 1:1 to metformin versus observation (OBS), we assessed change in the frequencies of T cell activation (CD38⁺HLA-DR⁺) and NCR [programmed cell death protein 1 (PD1), T cell immunoreceptor with Ig and ITIM domains (TIGIT), and T cell mucin-domain containing-3 (TIM3)]. No differences in 24-week change were seen between arms in CD4 or CD8 T cells, in the CD4/CD8 ratio, or in activated (CD38⁺HLA-DR⁺) CD4 or CD8 T cells. However, metformin over 24 weeks led to decreases compared with OBS in single PD1⁺ (percent decrease: -9.6% vs. 7.5%, <i>p</i> = .015), in dual PD1⁺TIGIT⁺ (-15.0% vs. 10.4%, <i>p</i> = .002), and in triple PD1⁺TIGIT⁺TIM3⁺ (-24.0% vs. 8.1%, <i>p</i> = .041) CD4 T cells. Metformin led to no changes in CD8 T cell NCR frequencies. Metformin decreases the frequency of PD1⁺, PD1⁺TIGIT⁺, and PD1⁺TIGIT⁺TIM3⁺ expressing CD4 T cells. This may have relevance to HIV cure strategies and to efforts to mitigate the risk of chronic complications of HIV.