Current approaches to reducing the latent HIV reservoir entail first reactivating virus-containing cells to become visible to the immune system. A critical second step is killing these cells to reduce reservoir size. Endogenous cytotoxic T-lymphocytes (CTLs) may not be adequate because of cellular exhaustion and the evolution of CTL-resistant viruses. We have designed a universal CAR-T cell platform based on CTLs engineered to bind a variety of broadly neutralizing anti-HIV antibodies. We show that this platform, convertibleCAR-T cells, effectively kills HIV-infected, but not uninfected, CD4 T cells from blood, tonsil, or spleen and only when armed with anti-HIV antibodies. convertibleCAR-T cells also kill within 48 h more than half of the inducible reservoir found in blood of HIV-infected individuals on antiretroviral therapy. The modularity of convertibleCAR-T cell system, which allows multiplexing with several anti-HIV antibodies yielding greater breadth and control, makes it a promising tool for attacking the latent HIV reservoir.
Keywords: CAR-T; HIV latency; MicAbody; T cell therapy; bNAb; broadly neutralizing HIV antibodies; convertibleCAR-T; reduce-and-control; reservoir; shock-and-kill.
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Conflict of interest statement
Declaration of Interests
None of the Gladstone/UCSF scientists have a commercial relationship with Xyphos Biosciences, Inc. KCK is an employee of Xyphos Biosciences, SRW is an employee and shareholder of Xyphos Biosciences, KL and NK are members of the Xyphos Biosciences scientific advisory board and DWM is a founder of Xyphos Biosciences, a shareholder, and member of its scientific advisory board. A patent application has been filed related to this work.
Chimeric Antigen Receptor T Cells Guided by the Single-Chain Fv of a Broadly Neutralizing Antibody Specifically and Effectively Eradicate Virus Reactivated From Latency in CD4+ T Lymphocytes Isolated From HIV-1-Infected Individuals Receiving Suppressive Combined Antiretroviral TherapyB Liu et al. J Virol 90 (21), 9712-9724. PMID 27535056.The presence of latently infected cells remains a key obstacle to the development of a functional HIV-1 cure. Reactivation of dormant viruses is possible with latency-rev …
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