Abstract
An effective strategy to cure HIV will likely require a potent and sustained antiviral T cell response. Here we explored the utility of chimeric antigen receptor (CAR) T cells, expressing the CD4 ectodomain to confer specificity for the HIV envelope, to mitigate HIV-induced pathogenesis in bone marrow, liver, thymus (BLT) humanized mice. CAR T cells expressing the 4-1BB/CD3-ζ endodomain were insufficient to prevent viral rebound and CD4+ T cell loss after the discontinuation of antiretroviral therapy. Through iterative improvements to the CAR T cell product, we developed Dual-CAR T cells that simultaneously expressed both 4-1BB/CD3-ζ and CD28/CD3-ζ endodomains. Dual-CAR T cells exhibited expansion kinetics that exceeded 4-1BB-, CD28- and third-generation costimulated CAR T cells, elicited effector functions equivalent to CD28-costimulated CAR T cells and prevented HIV-induced CD4+ T cell loss despite persistent viremia. Moreover, when Dual-CAR T cells were protected from HIV infection through expression of the C34-CXCR4 fusion inhibitor, these cells significantly reduced acute-phase viremia, as well as accelerated HIV suppression in the presence of antiretroviral therapy and reduced tissue viral burden. Collectively, these studies demonstrate the enhanced therapeutic potency of a novel Dual-CAR T cell product with the potential to effectively treat HIV infection.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal, Humanized / immunology
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Antibodies, Monoclonal, Humanized / pharmacology
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Bone Marrow / immunology
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Bone Marrow / virology
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CD3 Complex / antagonists & inhibitors
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CD4 Antigens / administration & dosage
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CD4 Antigens / immunology*
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Gene Expression Regulation / immunology
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HIV Envelope Protein gp41 / antagonists & inhibitors
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HIV Envelope Protein gp41 / immunology
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HIV Infections / immunology
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HIV Infections / pathology
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HIV Infections / therapy*
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HIV Infections / virology
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HIV-1 / immunology
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HIV-1 / pathogenicity
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Humans
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Immunotherapy, Adoptive*
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Liver / immunology
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Liver / virology
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Mice
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Peptide Fragments / antagonists & inhibitors
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Peptide Fragments / immunology
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Protein Domains / immunology
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Receptors, CXCR4 / antagonists & inhibitors
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Receptors, CXCR4 / immunology
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Receptors, Chimeric Antigen / administration & dosage
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Receptors, Chimeric Antigen / immunology*
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T-Lymphocytes / immunology
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Thymus Gland / immunology
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Thymus Gland / virology
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / antagonists & inhibitors
Substances
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Antibodies, Monoclonal, Humanized
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CD3 Complex
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CD3 antigen, zeta chain
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CD4 Antigens
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CXCR4 protein, mouse
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HIV Envelope Protein gp41
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Peptide Fragments
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Receptors, CXCR4
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Receptors, Chimeric Antigen
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Tumor Necrosis Factor Receptor Superfamily, Member 9
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peptide C34