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

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 cel...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519347/
https://www.ncbi.nlm.nih.gov/pubmed/32900948
http://dx.doi.org/10.1073/pnas.2008615117
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author 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.
author_facet 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.
author_sort Painter, Mark M.
collection PubMed
description 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.
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spelling pubmed-75193472020-10-07 Concanamycin A counteracts HIV-1 Nef to enhance immune clearance of infected primary cells by cytotoxic T lymphocytes 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. Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2020-09-22 2020-09-08 /pmc/articles/PMC7519347/ /pubmed/32900948 http://dx.doi.org/10.1073/pnas.2008615117 Text en Copyright © 2020 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
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.
Concanamycin A counteracts HIV-1 Nef to enhance immune clearance of infected primary cells by cytotoxic T lymphocytes
title Concanamycin A counteracts HIV-1 Nef to enhance immune clearance of infected primary cells by cytotoxic T lymphocytes
title_full Concanamycin A counteracts HIV-1 Nef to enhance immune clearance of infected primary cells by cytotoxic T lymphocytes
title_fullStr Concanamycin A counteracts HIV-1 Nef to enhance immune clearance of infected primary cells by cytotoxic T lymphocytes
title_full_unstemmed Concanamycin A counteracts HIV-1 Nef to enhance immune clearance of infected primary cells by cytotoxic T lymphocytes
title_short Concanamycin A counteracts HIV-1 Nef to enhance immune clearance of infected primary cells by cytotoxic T lymphocytes
title_sort concanamycin a counteracts hiv-1 nef to enhance immune clearance of infected primary cells by cytotoxic t lymphocytes
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519347/
https://www.ncbi.nlm.nih.gov/pubmed/32900948
http://dx.doi.org/10.1073/pnas.2008615117
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