Persistence of CMV-specific anti-HIV CAR T cells after adoptive immunotherapy

The success of chimeric antigen receptor (CAR)-T cell (Tc) immunotherapy in refractory B-cell acute lymphoblastic leukemia (B-ALL) suggests adaptation of this strategy toward HIV. Because cytomegalovirus (CMV) vaccine vectors generated Tc responses that controlled viral replication, these studies aim to genetically modify CMV-specific Tc with HIV-CAR2 vectors and link HIV immunotherapy to persistent CMV antigen stimulation. To mimic a clinical scenario, rhesus macaques were challenged with the CCR5-tropic simian/human immunodeficiency virus (SHIV-D) prior to antiretroviral therapy (ART). Autologous CMV-specific Tc were transduced with the control CEA-CAR2 or CD4-CAR2/maC46 vectors and reinfused. After stopping ART, the plasma viral load (PVL) in the control rebounded and was sustained above 1.7 × 10⁴ copies/mL; PVL in CD4-CAR2-treated animals was delayed up to 6 weeks and 10-fold lower. The CD4 CAR-Tc frequency peaked at day 7 and was detected in lymphoid tissues at 6 weeks. Both CEA-CAR2 and CD4-CAR2 persisted in PBMCs for about 2 years, which indicates that the CMV-specific CAR Tc were maintained based on their CMV specificity. However, long-term PVL was stable in all animals. Thus, CMV-specific CAR-Tc were active initially, persisted long term, but failed to control viral replication.IMPORTANCEBecause of latent viral reservoirs and a dysfunctional immune response, HIV replication rebounds when antiretroviral therapy is interrupted. Therefore, cytomegalovirus (CMV)-specific Tc were genetically modified with anti-HIV CD4-CAR2 vectors to link the targeting of the HIV envelope to the persistent CMV immune response. In this clinical scenario with simian/human immunodeficiency virus (SHIV) challenge and antiretroviral therapy (ART) suppression, early activity of the CAR Tc delayed rebound in the rhesus macaque/SHIV challenge model. However, even with long-term persistence of CAR Tc in the blood, control of viral replication was not achieved. These data suggest that CAR Tc will require additional interventions to cure HIV infection.