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

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.

SUBMITTER: Painter MM

PROVIDER: S-EPMC7519347 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Painter Mark M MM Zimmerman Gretchen E GE Merlino Madeline S MS Robertson Andrew W AW Terry Valeri H VH Ren Xuefeng X McLeod Megan R MR Gomez-Rodriguez Lyanne L Garcia Kirsten A KA Leonard Jolie A JA Leopold Kay E KE Neevel Andrew J AJ Lubow Jay J Olson Eli E Piechocka-Trocha Alicja A Collins David R DR Tripathi Ashootosh A Raghavan Malini M Walker Bruce D BD Hurley James H JH Sherman David H DH Collins Kathleen L KL

Proceedings of the National Academy of Sciences of the United States of America 20200908 38

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 subna ...[more]

PMID: 32900948

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Project description:Different vaccine approaches cope with HIV-1 diversity, ranging from centralized(1-4) to variability-encompassing(5-7) antigens. For all these strategies, a concern remains: how does HIV-1 diversity impact epitope recognition by the immune system? We studied the relationship between HIV-1 diversity and CD8(+) T Lymphocytes (CTL) targeting of HIV-1 subtype B Nef using 944 peptides (10-mers overlapping by nine amino acids (AA)) that corresponded to consensus peptides and their most common variants in the HIV-1-B virus population. IFN-? ELISpot assays were performed using freshly isolated PBMC from 26 HIV-1-infected persons. Three hundred and fifty peptides elicited a response in at least one individual. Individuals targeted a median of 7 discrete regions. Overall, 33% of responses were directed against viral variants but not elicited against consensus-based test peptides. However, there was no significant relationship between the frequency of a 10-mer in the viral population and either its frequency of recognition (Spearman's correlation coefficient ? = 0.24) or the magnitude of the responses (? = 0.16). We found that peptides with a single mutation compared to the consensus were likely to be recognized (especially if the change was conservative) and to elicit responses of similar magnitude as the consensus peptide. Our results indicate that cross-reactivity between rare and frequent variants is likely to play a role in the expansion of CTL responses, and that maximizing antigenic diversity in a vaccine may increase the breadth and depth of CTL responses. However, since there are few obvious preferred pathways to virologic escape, the diversity that may be required to block all potential escape pathways may be too large for a realistic vaccine to accommodate. Furthermore, since peptides were not recognized based on their frequency in the population, it remains unclear by which mechanisms variability-inclusive antigens (i.e., constructs enriched with frequent variants) expand CTL recognition.

Dataset Information

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

Publications

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

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