Project Summary/Abstract
HIV/AIDS is a chronic infectious disease that affects around 37 million people worldwide. CD8 T cells play a
critical role in controlling HIV infection. However, CD8 T cells become exhausted over time due to continuous
stimulation. Exhausted HIV-specific CD8 T cells, characterized by elevated expression of inhibitory receptors
(e.g. PD-1), positively correlate with higher viral load, impaired T cell function, and disease progression. In HIV
and other chronic viral infections, exhausted antigen-specific CD8 T cells expressing PD-1 can create a
suppressive environment suggesting that such cells not only have a direct role in disease progression but can
cross-talk with other immune cells to impair their function. Chronic HIV infection dysregulates T cell energy
metabolism. HIV-specific CD8 T cells isolated from infected individuals exhibit elevated mitochondrial stress
which is still apparent years after antiretroviral therapy (ART). PD-1 expression on T cells is associated with
mitochondrial stress. PD-1-mediated signaling dysregulates T cell mitochondrial energetics by reducing
glycolysis and shifting towards fatty acid b-oxidation and oxidative phosphorylation (OxPhos). Metformin is an
FDA-approved drug that dampens OxPhos by inhibiting mitochondrial complex I. To date, most studies
investigating metformin use in HIV+ individuals are often in the presence of ART. It has yet to be explored how
modulating energy metabolism with metformin impacts host immunity in an ART-naïve setting. HIV not only
impairs immune control of the viral infection, but also increases susceptibility to opportunistic infections. People
living with HIV are incredibly susceptible to the tuberculosis-causing bacilli, Mycobacterium tuberculosis (Mtb).
We previously showed SIV-infected Mauritian cynomolgus macaques (MCM) to be more susceptible to Mtb,
which we attributed to immunologic impairment by preexisting SIV infection. Therefore, Mtb challenge is a
stringent assessment of host defenses and, given the prevalence of HIV/Mtb co-infection, has great relevance
to global health.
In this K01 proposal, we will identify pathways involved in energy metabolism in CD8 T cells during chronic HIV
infection and reveal their role in T cell exhaustion using our established MCM model of HIV. We will use a
comprehensive analytic approach that combines single cell RNA sequencing, metabolic assays, and flow
cytometry to assess the role of T cell metabolism in SIV-infected MCM. We will alter metabolism using metformin
to reprogram CD8 T cells and determine whether this metabolic reprogramming improves host immunity by
challenging SIV+ animals with Mtb.