HIV-Resistant and HIV-Specific CAR-Modified CD4 + T Cells Mitigate HIV Disease Progression and Confer CD4 + T Cell Help In Vivo

Mol Ther. 2020 Jul 8;28(7):1585-1599. doi: 10.1016/j.ymthe.2020.05.012. Epub 2020 May 15.

Abstract

HIV infection preferentially depletes HIV-specific CD4+ T cells, thereby impairing antiviral immunity. In this study, we explored the therapeutic utility of adoptively transferred CD4+ T cells expressing an HIV-specific chimeric antigen receptor (CAR4) to restore CD4+ T cell function to the global HIV-specific immune response. We demonstrated that CAR4 T cells directly suppressed in vitro HIV replication and eliminated virus-infected cells. Notably, CAR4 T cells containing intracellular domains (ICDs) derived from the CD28 receptor family (ICOS and CD28) exhibited superior effector functions compared to the tumor necrosis factor receptor (TNFR) family ICDs (CD27, OX40, and 4-1BB). However, despite demonstrating limited in vitro efficacy, only HIV-resistant CAR4 T cells expressing the 4-1BBζ ICD exhibited profound expansion, concomitant with reduced rebound viremia after antiretroviral therapy (ART) cessation and protection of CD4+ T cells (CAR-) from HIV-induced depletion in humanized mice. Moreover, CAR4 T cells enhanced the in vivo persistence and efficacy of HIV-specific CAR-modified CD8+ T cells expressing the CD28ζ ICD, which alone exhibited poor survival. Collectively, these studies demonstrate that HIV-resistant CAR4 T cells can directly control HIV replication and augment the virus-specific CD8+ T cell response, highlighting the therapeutic potential of engineered CD4+ T cells to engender a functional HIV cure.

Keywords: C34-CXCR4; IL-2; IL-21; T cell help; TIGIT; chimeric antigen receptor; costimulation; in vivo model of HIVPD-1.

Publication types

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

MeSH terms

  • Animals
  • CD28 Antigens / chemistry*
  • CD28 Antigens / genetics
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / transplantation*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cells, Cultured
  • Disease Models, Animal
  • Disease Progression
  • Drug Resistance, Viral
  • HIV / immunology
  • HIV / physiology*
  • HIV Infections / immunology
  • HIV Infections / therapy*
  • HIV-1 / immunology
  • Humans
  • Immunotherapy, Adoptive
  • Inducible T-Cell Co-Stimulator Protein / chemistry*
  • Inducible T-Cell Co-Stimulator Protein / genetics
  • Mice
  • Protein Domains
  • Receptors, Chimeric Antigen / genetics
  • Receptors, Chimeric Antigen / metabolism*
  • Treatment Outcome
  • Virus Replication

Substances

  • CD28 Antigens
  • ICOS protein, human
  • Inducible T-Cell Co-Stimulator Protein
  • Receptors, Chimeric Antigen