Targeting γδ T cells for immunotherapy of HIV disease.

Disruption of circulating γδ T-cell populations is an early and common outcome of HIV infection. T-cell receptor (TCR)-γ2δ2 cells (expressing the Vγ2 and Vδ2 chains of the γδ TCR) are depleted, even though they are minimally susceptible to direct HIV infection, and exemplify indirect cell depletion mechanisms that are important in the progression to AIDS. Among individuals with common or normally progressing HIV disease, the loss of TCR-γ2δ2 cells has a broad impact on viral immunity, control of opportunistic pathogens and resistance to malignant disease. Advanced HIV disease can result in complete loss of TCR-γ2δ2 cells that are not recovered even during antiretroviral therapy with complete virus suppression. However, normal levels of TCR-γ2δ2 were observed among natural virus suppressors (low or undetectable virus without antiretroviral therapy) irrespective of their MHC haplotype, consistent with their disease-free status. The pattern of loss and recovery of TCR-γ2δ2 cells revealed their unique features and functional capacities, and encourage the development of immune-based therapies to activate and expand this T-cell subset. New research has identified drugs that might reconstitute the TCR-γ2δ2 population, recover their functional contributions, and improve control of HIV replication and disease. Here, we review research on HIV and TCR-γδ T cells to highlight the consequences of depleting this subset and the unique features of TCR-γδ biology that argue in favor of clinical strategies to reconstitute this T-cell subset in individuals with HIV/AIDS.