Elevated glutamate impedes anti-HIV-1 CD8 + T cell responses in HIV-1-infected individuals on antiretroviral therapy

Abstract

CD8 + T cells are essential for long-lasting HIV-1 control and have been harnessed to develop therapeutic and preventive approaches for people living with HIV-1 (PLWH). HIV-1 infection induces marked metabolic alterations. However, it is unclear whether these changes affect the anti-HIV function of CD8 + T cells. Here, we show that PLWH exhibit higher levels of plasma glutamate than healthy controls. In PLWH, glutamate levels positively correlate with HIV-1 reservoir and negatively correlate with the anti-HIV function of CD8 + T cells. Single-cell metabolic modeling reveals glutamate metabolism is surprisingly robust in virtual memory CD8 + T cells (TVM). We further confirmed that glutamate inhibits TVM cells function via the mTORC1 pathway in vitro. Our findings reveal an association between metabolic plasticity and CD8 + T cell-mediated HIV control, suggesting that glutamate metabolism can be exploited as a therapeutic target for the reversion of anti-HIV CD8 + T cell function in PLWH.

Examining Chronic Inflammation, Immune Metabolism, and T Cell Dysfunction in HIV Infection

“…As a result, increased glucose metabolic activity and increased Glut1 expression are associated with CD4 T cell activation and depletion during chronic HIV infection in PLWHs, and are not completely normalized by ART [ 141 ]. Dysregulation of glutamine metabolism in HIV infection can lead to immune cell dysfunction, as evidenced by a negative correlation between glutamine levels and the production of cytokines and chemokines by CD8+ T cells [ 142 , 143 ]; meanwhile, CD4 cell count is inversely correlated with both glutamine and glucose concentrations [ 144 ]. In addition, the metabolism of amino acids such as tryptophan and arginine, which are crucial for immune cell function [ 145 , 146 ], are also impaired during HIV infection.…”