Robust expansion of HIV CAR T cells following antigen boosting in ART-suppressed nonhuman primates

Blood. 2020 Oct 8;136(15):1722-1734. doi: 10.1182/blood.2020006372.


Chimeric antigen receptor (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 antiretroviral therapy (ART)-suppressed patients in contrast to those with hematologic malignancies. Using our well-established nonhuman primate model of ART-suppressed HIV-1 infection, we tested 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 4 simian/HIV-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; after ART treatment interruption, viral rebound was significantly delayed compared with controls (P = .014). In 2 animals with declining CAR T cells, rhesusized anti-programmed cell death protein 1 (PD-1) antibody was administered 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 show 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Viral / immunology*
  • Antiretroviral Therapy, Highly Active / adverse effects
  • Antiretroviral Therapy, Highly Active / methods
  • Disease Models, Animal
  • HIV Infections / drug therapy
  • HIV Infections / immunology*
  • HIV Infections / virology
  • HIV-1 / immunology*
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Proteins / genetics
  • Immune Checkpoint Proteins / metabolism
  • Immunocompromised Host*
  • Macaca mulatta
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Chimeric Antigen / immunology*
  • Simian Immunodeficiency Virus / immunology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*


  • Antigens, Viral
  • Immune Checkpoint Inhibitors
  • Immune Checkpoint Proteins
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen