Do T cells from HIV-infected individuals have normal metabolic function?

Abstract

Untreated HIV infection is characterized by generalized immune activation, T cell dysfunction, and ultimately the exhaustion of HIV-specific CD8 T cell responses. Durable virus suppression resulting from anti-retroviral therapy (ART) is associated with greatly improved immune function, but some phenotypic and functional abnormalities persist even after years of suppressive ART. We have observed that, relative to HIV-seronegative individuals, CD8 T cells from HIV+ participants on ART are skewed toward a more effector-like (T-bethigh Eomeslow) phenotype and have significantly reduced proliferative capacity in response to antigenic stimulation. Metabolic pathways play a key role in shaping T cell maturation, phenotype, and function, and the ability to produce ATP via both glycolytic and oxidative phosphorylation (mitochondrial) pathways is critical to T cell function and longevity. However, whether underlying metabolic abnormalities contribute to residual CD8 T cell dysfunction in HIV+ individuals on ART has not been fully explored. Here we compare the metabolic phenotype of T cells from HIV+ participants on ART with those from HIV-seronegative participants. We are using MitoTracker® dyes to assess mitochondrial mass and polarization in T cell memory subsets, ex vivo and in response to antigen, and measuring expression of the glucose transporter GLUT1 and the mitochondrial biogenesis master regulator PGC-1α in different CD8 T cell effector subsets. Our findings will inform whether phenotypic and functional abnormalities in CD8 T cells from HIV+ individuals on ART reflect underlying metabolic dysfunction and if metabolic interventions could improve T cell function.