Key Points

  • Exogenous cell-based antigen overcomes endogenous low-antigen conditions to boost virus-specific CAR T cells in vivo

  • CAR T cells can control viral replication following ART withdrawal and can be reactivated by anti-PD-1 administration

CAR T cells targeting CD19+ hematologic malignancies have rapidly emerged as a promising, novel therapy. In contrast, results from the few CAR T-cell studies for infectious diseases such as HIV-1 have been less convincing. These challenges are likely due to the low level of antigen present in ART-suppressed patients in contrast to those with hematologic malignancies. Here we tested in our well-established nonhuman primate model of ART-suppressed HIV-1 infection strategies to overcome these limitations and challenges. We first optimized CAR T cell production to maintain central memory subsets, consistent with current clinical paradigms. We hypothesized that additional exogenous antigen might be required in an ART-suppressed setting to aid expansion and persistence of CAR T cells. Thus, we studied four simian/human immunodeficiency virus (SHIV)-infected, ART-suppressed rhesus macaques infused with virus-specific CD4CAR T cells, followed by supplemental infusion of cell-associated HIV-1 envelope (Env). Env boosting led to significant and unprecedented expansion of virus-specific CAR+ T-cells in vivo; following ART treatment interruption, viral rebound was significantly delayed compared to controls (p=0.014). In two animals with declining CAR T cells, we administered rhesusized anti-PD-1 antibody to reverse PD-1-dependent immune exhaustion. Immune checkpoint blockade triggered expansion of exhausted CAR T cells and concordantly lowered viral loads to undetectable levels. These results demonstrate that supplemental cell-associated antigen enables robust expansion of CAR T-cells in an antigen-sparse environment. To our knowledge, this is the first study to show expansion of virus-specific CAR T cells in infected, suppressed hosts, and delay/control of viral recrudescence.

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