The Role of γδ T Cells in HIV Persistence and Cure
Open Access DepositedAcquisition of Human Immunodeficiency Virus (HIV) results in a systemic, chronic infection of the immune system. Antiretroviral therapy (ART) effectively suppresses viral replication, but it does not eradicate HIV from the body due to a reservoir of long-lived, infected cells harboring latent provirus. Efforts to characterize the latent reservoir have focused on CD4+ T cells, however, recent evidence suggests additional cell types may contribute to HIV persistence especially within mucosal tissue. Identification of novel cell types that harbor latent provirus is paramount to both understanding HIV pathogenesis and developing an efficacious cure. In this work, we describe the role of an unconventional subset of lymphocytes known as gamma delta (γδ) T cells within persistent HIV infection. First, we demonstrated that the two major subsets of human γδ T cells, Vδ1 and Vδ2, are distinct lineages with dissimilar phenotypes, gene expression profiles, and effector functions that underlie their unique contributions to immunity. In subsequent studies, we describe the juxtaposing role for each γδ T cell subset in HIV persistence. We identified a subset of highly cytotoxic Vδ1 T cell effectors within the peripheral blood of ART-suppressed individuals that retain potent anti-HIV functions. Conversely, we found a high prevalence of CD4+Vδ1 T cells in the gastrointestinal mucosa are a significant contributor to the latent cellular reservoir throughout ART. In a separate study, we show that durable ART restores Vδ2 T cell cytotoxic effector functions to a level comparable with people living without HIV-1 (PWOH). Lastly, we demonstrate that allogeneic Vδ2 T cells from PWOH can specifically target and kill reactivated, latently infected CD4+ T cells providing preliminary evidence for a novel immunotherapy aimed at curing persistent HIV infection. Collectively, this work highlights a previously underappreciated, yet critical role for γδ T cells in contributing to viral persistence and their potential use in efforts to eradicate HIV.
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