A Trispecific Anti-HIV Chimeric Antigen Receptor Containing the CCR5 N-Terminal Region

Anti-HIV chimeric antigen receptors (CARs) promote direct killing of infected cells, thus offering a therapeutic approach aimed at durable suppression of infection emerging from viral reservoirs. CD4-based CARs represent a favored option, since they target the essential conserved primary receptor bi...

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Bibliographic Details
Published in:Frontiers in cellular and infection microbiology 2020-05, Vol.10, p.242-242
Main Authors: Hajduczki, Agnes, Danielson, David T, Elias, David S, Bundoc, Virgilio, Scanlan, Aaron W, Berger, Edward A
Format: Article
Language:English
Subjects:
CD4
CD8-Positive T-Lymphocytes - metabolism
cell therapy
Cellular and Infection Microbiology
chimeric antigen receptor
HIV
HIV functional cure
HIV Infections - therapy
HIV-1
Humans
immunotherapy
Immunotherapy, Adoptive
Protein Binding
Receptors, CCR5 - metabolism
Receptors, Chimeric Antigen - metabolism
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Summary:Anti-HIV chimeric antigen receptors (CARs) promote direct killing of infected cells, thus offering a therapeutic approach aimed at durable suppression of infection emerging from viral reservoirs. CD4-based CARs represent a favored option, since they target the essential conserved primary receptor binding site on the HIV envelope glycoprotein (Env). We have previously shown that adding a second Env-binding moiety, such as the carbohydrate recognition domain of human mannose-binding lectin (MBL) that recognizes the highly conserved oligomannose patch on gp120, increases CAR potency in an HIV suppression assay; moreover it reduces the undesired capacity for the CD4 of the CAR molecule to act as an entry receptor, thereby rendering CAR-expressing CD8 T cells susceptible to infection. Here, we further improve the bispecific CD4-MBL CAR by adding a third targeting moiety against a distinct conserved Env determinant, i.e. a polypeptide sequence derived from the N-terminus of the HIV coreceptor CCR5. The trispecific CD4-MBL-R5Nt CAR displays enhanced anti-HIV potency compared to the CD4-MBL CAR, as well as undetectable HIV entry receptor activity. The high anti-HIV potency of the CD4-MBL-R5Nt CAR, coupled with its all-human composition and absence of immunogenic variable regions associated with antibody-based CARs, offer promise for the trispecific construct in therapeutic approaches seeking durable drug-free HIV remission.
ISSN:2235-2988
2235-2988
DOI:10.3389/fcimb.2020.00242