concanamycin-a and HIV-Infections

concanamycin-a has been researched along with HIV-Infections* in 2 studies

Other Studies

2 other study(ies) available for concanamycin-a and HIV-Infections

ArticleYear
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, 09-22, Volume: 117, Issue: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 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.

    Topics: Cells, Cultured; Histocompatibility Antigens Class I; HIV Infections; HIV-1; Host-Pathogen Interactions; Humans; Macrolides; nef Gene Products, Human Immunodeficiency Virus; T-Lymphocytes, Cytotoxic

2020
Multiple effector functions mediated by human immunodeficiency virus-specific CD4(+) T-cell clones.
    Journal of virology, 2001, Volume: 75, Issue:20

    Mounting evidence suggests that human immunodeficiency virus type 1 (HIV-1) Gag-specific T helper cells contribute to effective antiviral control, but their functional characteristics and the precise epitopes targeted by this response remain to be defined. In this study, we generated CD4(+) T-cell clones specific for Gag from HIV-1-infected persons with vigorous Gag-specific responses detectable in peripheral blood mononuclear cells. Multiple peptides containing T helper epitopes were identified, including a minimal peptide, VHAGPIAG (amino acids 218 to 226), in the cyclophilin binding domain of Gag. Peptide recognition by all clones examined induced cell proliferation, gamma interferon (IFN-gamma) secretion, and cytolytic activity. Cytolysis was abrogated by concanamycin A and EGTA but not brefeldin A or anti-Fas antibody, implying a perforin-mediated mechanism of cell lysis. Additionally, serine esterase release into the extracellular medium, a marker for cytolytic granules, was demonstrated in an antigen-specific, dose-dependent fashion. These data indicate that T helper cells can target multiple regions of the p24 Gag protein and suggest that cytolytic activity may be a component of the antiviral effect of these cells.

    Topics: Amino Acid Sequence; Anti-Bacterial Agents; Antibodies; Brefeldin A; CD4-Positive T-Lymphocytes; Clone Cells; Cyclophilins; Cytotoxicity, Immunologic; Dose-Response Relationship, Drug; Egtazic Acid; Epitopes; fas Receptor; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Interferon-gamma; Macrolides; Male; Middle Aged; Molecular Sequence Data; Protein Binding; T-Lymphocytes, Helper-Inducer

2001