MAIT Cell Loss and Reconstitution in HIV-1 Disease

Mucosa-associated invariant T (MAIT) cells are unconventional innate-like T cells that recognize microbial riboflavin-related metabolites presented by the evolutionarily conserved MHC class I-related (MR1) molecule. MAIT cells are abundant in circulation and mucosal tissues and are poised to mount rapid effector responses against diverse microbial organisms. Despite the absence of virally encoded riboflavin-related metabolite antigens, MAIT cells can respond to viral infections in an MR1-independent and cytokine-dependent manner. In chronic HIV-1 infection, MAIT cells are persistently depleted and functionally exhausted. Long-term effective combination antiretroviral therapy can only partially rescue MAIT cell numbers and dysfunction. Our understanding of the mechanisms underlying MAIT cell loss in HIV-1 infection is still incomplete, and to date, few effective strategies to recover their loss in humans are available. Here, we review current knowledge concerning the mechanisms of MAIT cell responses and loss in different stages of HIV-1 infection and how we may potentially develop strategies to restore these cells in the clinical setting. We further discuss novel strategies that may aid future investigations into MAIT cell immunobiology in HIV-1 infection, including the potential use of three-dimensional organoid models to dissect the mechanisms of MAIT cell depletion and to explore interventions that may restore their numbers and functionality.