Multispecific anti-HIV duoCAR-T cells display broad in vitro antiviral activity and potent in vivo elimination of HIV-infected cells in a humanized mouse model

Abstract

Adoptive immunotherapy using chimeric antigen receptor–modified T cells (CAR-T) has made substantial contributions to the treatment of certain B cell malignancies. Such treatment modalities could potentially obviate the need for long-term antiretroviral drug therapy in HIV/AIDS. Here, we report the development of HIV-1–based lentiviral vectors that encode CARs targeting multiple highly conserved sites on the HIV-1 envelope glycoprotein using a two-molecule CAR architecture, termed duoCAR. We show that transduction with lentiviral vectors encoding multispecific anti-HIV duoCARs confer primary T cells with the capacity to potently reduce cellular HIV infection by up to 99% in vitro and >97% in vivo. T cells are the targets of HIV infection, but the transduced T cells are protected from genetically diverse HIV-1 strains. The CAR-T cells also potently eliminated PBMCs infected with broadly neutralizing antibody-resistant HIV strains, including VRC01/3BNC117-resistant HIV-1. Furthermore, multispecific anti-HIV duoCAR-T cells demonstrated long-term control of HIV infection in vivo and prevented the loss of CD4+T cells during HIV infection using a humanized NSG mouse model of intrasplenic HIV infection. These data suggest that multispecific anti-HIV duoCAR-T cells could be an effective approach for the treatment of patients with HIV-1 infection.

Broadly neutralizing antibodies for HIV-1: efficacies, challenges and opportunities

“…Furthermore, chimeric antigen receptor (CAR)-T cells, with the extracellular domain from the singlechain variable fragment of bNAb, can effectively kill reactivated HIV-1-infected CD4 + T cells [86]. Multispecific anti-HIV duoCAR-T cells display potent elimination of HIV-infected cells and mitigate CD4 + T cell loss in a humanized mouse model of intrasplenic HIV infection [87]. A newly designed convertibleCAR-T cell system capable of binding to a variety of bNAbs yields greater breadth and control, representing a potential strategy for targeting the latent HIV-1 reservoir [88].…”

Advances in Developing CAR T-Cell Therapy for HIV Cure

“…Additionally, it was observed that CAR T cells persisted at high levels for at least 6 months in the cerebrospinal fluid (CSF) (106), a compartment that contains a significant but hard-to-reach reservoir of HIV (107). A recent study showed that primary T cells transduced with a multispecific CAR (targeting both the gp120 CD4-binding site and the gp120 co-receptor-binding site) had the ability to potently reduce cellular HIV infection by up to 99% in vitro and >97% in vivo (108).…”

Understanding and Modulating Immunity With Cell Reprogramming

“…These studies are now re-emerging as the improvements in CAR design done for cancer are being translated and adapted to fight HIV infection [reviewed by (217)]. Recently, multispecific anti-HIV CAR T cells targeting different portions of the HIV envelope protein were shown to control HIV infection in a humanized mouse model (218). iPSCderived NK cells, unmodified or carrying HIV-targeted chimeric receptor, were also developed and were shown to suppress HIV replication and CD4+ T cell infection in vitro and in vivo (219,220).…”