Ex vivo–expanded allogeneic Vδ2 T cells specifically reduce reservoirs of HIV-1 following latency reversal

Latently infected cells persist in people living with HIV (PWH) despite suppressive antiretroviral therapy (ART) and evade immune clearance. "Shock and Kill" cure strategies are hampered by insufficient enhancement of targeted immune responses following latency reversal. We previously demonstrated that autologous Vδ2 T cells from PWH retain anti-HIV activity and can reduce CD4+ T cell reservoirs, although their use in cure approaches is limited due to their dual role as a viral reservoir. However, promising clinical data in oncology shows that their unique MHC-unrestricted antigen recognition affords potent on-target cytotoxicity in the absence of graft-versus-host disease when used as an allogeneic adoptive cell therapy modality. Here, we found expanded allogeneic Vδ2 T cells specifically eliminated HIV-infected CD4+ T cells and monocyte-derived macrophages (MDM), overcoming inherent resistance to killing by other cell types such as NK and CD8+ T cells. Notably, we demonstrated that allogeneic Vδ2 T cells recognized and eliminated the HIV-latent CD4+ T cell reservoir following latency reversal. Our study provides evidence for developing an allogeneic γδ T cell therapy for HIV cure and warrants preclinical investigation in combination approaches.