Concanamycin A counteracts HIV-1 Nef to enhance immune clearance of infected primary cells by cytotoxic T lymphocytes.

Proceedings of the National Academy of Sciences of the United States of America 2020 Sep 22

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Nef is an HIV-encoded accessory protein that enhances pathogenicity by down-regulating major histocompatibility class I (MHC-I) expression to evade killing by cytotoxic T lymphocytes (CTLs). A potent Nef inhibitor that restores MHC-I is needed to promote immune-mediated clearance of HIV-infected cells. We discovered that the plecomacrolide family of natural products restored MHC-I to the surface of Nef-expressing primary cells with variable potency. Concanamycin A (CMA) counteracted Nef at subnanomolar concentrations that did not interfere with lysosomal acidification or degradation and were nontoxic in primary cell cultures. CMA specifically reversed Nef-mediated down-regulation of MHC-I, but not CD4, and cells treated with CMA showed reduced formation of the Nef:MHC-I:AP-1 complex required for MHC-I down-regulation. CMA restored expression of diverse allotypes of MHC-I in Nef-expressing cells and inhibited Nef alleles from divergent clades of HIV and simian immunodeficiency virus, including from primary patient isolates. Lastly, we found that restoration of MHC-I in HIV-infected cells was accompanied by enhanced CTL-mediated clearance of infected cells comparable to genetic deletion of Nef. Thus, we propose CMA as a lead compound for therapeutic inhibition of Nef to enhance immune-mediated clearance of HIV-infected cells. Copyright © 2020 the Author(s). Published by PNAS.

Citation

Mark M Painter, Gretchen E Zimmerman, Madeline S Merlino, Andrew W Robertson, Valeri H Terry, Xuefeng Ren, Megan R McLeod, Lyanne Gomez-Rodriguez, Kirsten A Garcia, Jolie A Leonard, Kay E Leopold, Andrew J Neevel, Jay Lubow, Eli Olson, Alicja Piechocka-Trocha, David R Collins, Ashootosh Tripathi, Malini Raghavan, Bruce D Walker, James H Hurley, David H Sherman, Kathleen L Collins. Concanamycin A counteracts HIV-1 Nef to enhance immune clearance of infected primary cells by cytotoxic T lymphocytes. Proceedings of the National Academy of Sciences of the United States of America. 2020 Sep 22;117(38):23835-23846