Engineering HIV-Resistant, Anti-HIV Chimeric Antigen Receptor T Cells

• Published in: Molecular therapy 2017-03, Vol.25 (3), p.570-579
• Main Authors: Hale, Malika, Mesojednik, Taylor, Romano Ibarra, Guillermo S., Sahni, Jaya, Bernard, Alison, Sommer, Karen, Scharenberg, Andrew M., Rawlings, David J., Wagner, Thor A.
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; Antibodies, Neutralizing - genetics; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - metabolism; Antigens; Binding sites; CAR T cell; CCR5 protein; cell therapy; chimeric antigen receptor; Chimeric antigen receptors; Cytokines; Cytotoxicity; Cytotoxicity, Immunologic; Epitopes - immunology; Flow cytometry; gene editing; Gene Order; Gene therapy; Genetic Engineering; Genetic Vectors - genetics; Genome editing; Glycoproteins; HIV; HIV Antibodies - genetics; HIV Antibodies - immunology; HIV Antibodies - metabolism; HIV Envelope Protein gp120 - immunology; HIV Infections - genetics; HIV Infections - immunology; HIV Infections - therapy; HIV-1 - immunology; Homology; Human immunodeficiency virus; Humans; Immunotherapy; Infections; Lymphocyte Activation - immunology; Lymphocyte Subsets - immunology; Lymphocyte Subsets - metabolism; Lymphocytes; Lymphocytes T; Monoclonal antibodies; Mutation; Original; Proteins; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; Receptors, CCR5 - genetics; Receptors, CCR5 - metabolism; Recombinant Fusion Proteins; Recombination; Single-Chain Antibodies; T cell receptors; Virus Replication
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2016.12.023

The treatment or cure of HIV infection by cell and gene therapy has been a goal for decades. Recent advances in both gene editing and chimeric antigen receptor (CAR) technology have created new therapeutic possibilities for a variety of diseases. Broadly neutralizing monoclonal antibodies (bNAbs) with specificity for the HIV envelope glycoprotein provide a promising means of targeting HIV-infected cells. Here we show that primary human T cells engineered to express anti-HIV CARs based on bNAbs (HIVCAR) show specific activation and killing of HIV-infected versus uninfected cells in the absence of HIV replication. We also show that homology-directed recombination of the HIVCAR gene expression cassette into the CCR5 locus enhances suppression of replicating virus compared with HIVCAR expression alone. This work demonstrates that HIV immunotherapy utilizing potent bNAb-based single-chain variable fragments fused to second-generation CAR signaling domains, delivered directly into the CCR5 locus of T cells by homology-directed gene editing, is feasible and effective. This strategy has the potential to target HIV-infected cells in HIV-infected individuals, which might help in the effort to cure HIV. Rawlings, Wagner, and colleagues show that T cells expressing chimeric antigen receptors based on HIV-neutralizing antibodies can selectively clear HIV-infected cells in culture and demonstrate that the use of gene editing to protect therapeutic T cells from HIV infection can improve their efficacy.