1. Concanamycin A counteracts HIV-1 Nef to enhance immune clearance of infected primary cells by cytotoxic T lymphocytes.
- Author
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Painter, Mark M, Painter, Mark M, Zimmerman, Gretchen E, Merlino, Madeline S, Robertson, Andrew W, Terry, Valeri H, Ren, Xuefeng, McLeod, Megan R, Gomez-Rodriguez, Lyanne, Garcia, Kirsten A, Leonard, Jolie A, Leopold, Kay E, Neevel, Andrew J, Lubow, Jay, Olson, Eli, Piechocka-Trocha, Alicja, Collins, David R, Tripathi, Ashootosh, Raghavan, Malini, Walker, Bruce D, Hurley, James H, Sherman, David H, Collins, Kathleen L, Painter, Mark M, Painter, Mark M, Zimmerman, Gretchen E, Merlino, Madeline S, Robertson, Andrew W, Terry, Valeri H, Ren, Xuefeng, McLeod, Megan R, Gomez-Rodriguez, Lyanne, Garcia, Kirsten A, Leonard, Jolie A, Leopold, Kay E, Neevel, Andrew J, Lubow, Jay, Olson, Eli, Piechocka-Trocha, Alicja, Collins, David R, Tripathi, Ashootosh, Raghavan, Malini, Walker, Bruce D, Hurley, James H, Sherman, David H, and Collins, Kathleen L
- Abstract
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.
- Published
- 2020