Adoptive transfer of allogeneic gamma delta T cells promotes HIV replication in a humanized mouse model

Abstract

Gamma-delta ({gamma}{delta}) T cells recognize antigens in an MHC-independent manner, with demonstrable cytotoxicity against cancer and virally infected cells. Human immunodeficiency virus (HIV) infection severely depletes the V{gamma}9V{delta}2 (V{delta}2) subset of these T cells in most infected individuals, with the exception of elite controllers. The capacity of V{delta}2 cells to kill HIV-infected targets has been demonstrated in vitro, but this has not been verified in vivo. Here, we examined the immunotherapeutic potential of V{delta}2 cells in controlling HIV replication in vivo and provide the first characterization of reconstituted {gamma}{delta} T cell subsets in the peripheral blood and lymphoid tissue in a humanized mouse model. We demonstrate the depletion of V{delta}2 cells and increase in V{delta}1 cells in the blood following HIV infection, similar to that observed in HIV-infected humans. The functionality of human V{delta}2 cells isolated from humanized mice was confirmed via ex vivo expansion in response to zoledronate and IL-2 treatment. The adoptive transfer of activated V{delta}2 cells failed to control HIV infection in vivo but instead exacerbated viremia by serving as early targets for HIV infection. Our findings suggest that V{delta}2 cells play a critical and unappreciated role as early HIV targets of infection to promote viral dissemination.