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Differences in serum IgA responses to HIV-1 gp41 in elite controllers compared to viral suppressors on highly active antiretroviral therapy

Mechanisms responsible for natural control of human immunodeficiency type 1 (HIV) replication in elite controllers (EC) remain incompletely defined. To determine if EC generate high quality HIV-specific IgA responses, we used Western blotting to compare the specificities and frequencies of IgA to HI...

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Autores principales: Nabi, Rafiq, Moldoveanu, Zina, Wei, Qing, Golub, Elizabeth T., Durkin, Helen G., Greenblatt, Ruth M., Herold, Betsy C., Nowicki, Marek J., Kassaye, Seble, Cho, Michael W., Pinter, Abraham, Landay, Alan L., Mestecky, Jiri, Kozlowski, Pamela A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495342/
https://www.ncbi.nlm.nih.gov/pubmed/28671952
http://dx.doi.org/10.1371/journal.pone.0180245
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author Nabi, Rafiq
Moldoveanu, Zina
Wei, Qing
Golub, Elizabeth T.
Durkin, Helen G.
Greenblatt, Ruth M.
Herold, Betsy C.
Nowicki, Marek J.
Kassaye, Seble
Cho, Michael W.
Pinter, Abraham
Landay, Alan L.
Mestecky, Jiri
Kozlowski, Pamela A.
author_facet Nabi, Rafiq
Moldoveanu, Zina
Wei, Qing
Golub, Elizabeth T.
Durkin, Helen G.
Greenblatt, Ruth M.
Herold, Betsy C.
Nowicki, Marek J.
Kassaye, Seble
Cho, Michael W.
Pinter, Abraham
Landay, Alan L.
Mestecky, Jiri
Kozlowski, Pamela A.
author_sort Nabi, Rafiq
collection PubMed
description Mechanisms responsible for natural control of human immunodeficiency type 1 (HIV) replication in elite controllers (EC) remain incompletely defined. To determine if EC generate high quality HIV-specific IgA responses, we used Western blotting to compare the specificities and frequencies of IgA to HIV antigens in serum of gender-, age- and race-matched EC and aviremic controllers (HC) and viremic noncontrollers (HN) on highly active antiretroviral therapy (HAART). Concentrations and avidity of IgA to HIV antigens were measured using ELISA or multiplex assays. Measurements for IgG were performed in parallel. EC were found to have stronger p24- and V1V2-specific IgG responses than HN, but there were no IgG differences for EC and HC. In contrast, IgA in EC serum bound more frequently to gp160 and gag proteins than IgA in HC or HN. The avidity of anti-gp41 IgA was also greater in EC, and these subjects had stronger IgA responses to the gp41 heptad repeat region 1 (HR1), a reported target of anti-bacterial RNA polymerase antibodies that cross react with gp41. However, EC did not demonstrate greater IgA responses to E. coli RNA polymerase or to peptides containing the shared LRAI sequence, suggesting that most of their HR1-specific IgA antibodies were not induced by intestinal microbiota. In both EC and HAART recipients, the concentrations of HIV-specific IgG were greater than HIV-specific IgA, but their avidities were comparable, implying that they could compete for antigen. Exceptions were C1 peptides and V1V2 loops. IgG and IgA responses to these antigens were discordant, with IgG reacting to V1V2, and IgA reacting to C1, especially in EC. Interestingly, EC with IgG hypergammaglobulinemia had greater HIV-specific IgA and IgG responses than EC with normal total IgG levels. Heterogeneity in EC antibody responses may therefore be due to a more focused HIV-specific B cell response in some of these individuals. Overall, these data suggest that development of HIV-specific IgA responses and affinity maturation of anti-gp41 IgA antibodies occurs to a greater extent in EC than in subjects on HAART. Future studies will be required to determine if IgA antibodies in EC may contribute in control of viral replication.
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spelling pubmed-54953422017-07-18 Differences in serum IgA responses to HIV-1 gp41 in elite controllers compared to viral suppressors on highly active antiretroviral therapy Nabi, Rafiq Moldoveanu, Zina Wei, Qing Golub, Elizabeth T. Durkin, Helen G. Greenblatt, Ruth M. Herold, Betsy C. Nowicki, Marek J. Kassaye, Seble Cho, Michael W. Pinter, Abraham Landay, Alan L. Mestecky, Jiri Kozlowski, Pamela A. PLoS One Research Article Mechanisms responsible for natural control of human immunodeficiency type 1 (HIV) replication in elite controllers (EC) remain incompletely defined. To determine if EC generate high quality HIV-specific IgA responses, we used Western blotting to compare the specificities and frequencies of IgA to HIV antigens in serum of gender-, age- and race-matched EC and aviremic controllers (HC) and viremic noncontrollers (HN) on highly active antiretroviral therapy (HAART). Concentrations and avidity of IgA to HIV antigens were measured using ELISA or multiplex assays. Measurements for IgG were performed in parallel. EC were found to have stronger p24- and V1V2-specific IgG responses than HN, but there were no IgG differences for EC and HC. In contrast, IgA in EC serum bound more frequently to gp160 and gag proteins than IgA in HC or HN. The avidity of anti-gp41 IgA was also greater in EC, and these subjects had stronger IgA responses to the gp41 heptad repeat region 1 (HR1), a reported target of anti-bacterial RNA polymerase antibodies that cross react with gp41. However, EC did not demonstrate greater IgA responses to E. coli RNA polymerase or to peptides containing the shared LRAI sequence, suggesting that most of their HR1-specific IgA antibodies were not induced by intestinal microbiota. In both EC and HAART recipients, the concentrations of HIV-specific IgG were greater than HIV-specific IgA, but their avidities were comparable, implying that they could compete for antigen. Exceptions were C1 peptides and V1V2 loops. IgG and IgA responses to these antigens were discordant, with IgG reacting to V1V2, and IgA reacting to C1, especially in EC. Interestingly, EC with IgG hypergammaglobulinemia had greater HIV-specific IgA and IgG responses than EC with normal total IgG levels. Heterogeneity in EC antibody responses may therefore be due to a more focused HIV-specific B cell response in some of these individuals. Overall, these data suggest that development of HIV-specific IgA responses and affinity maturation of anti-gp41 IgA antibodies occurs to a greater extent in EC than in subjects on HAART. Future studies will be required to determine if IgA antibodies in EC may contribute in control of viral replication. Public Library of Science 2017-07-03 /pmc/articles/PMC5495342/ /pubmed/28671952 http://dx.doi.org/10.1371/journal.pone.0180245 Text en © 2017 Nabi et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Nabi, Rafiq
Moldoveanu, Zina
Wei, Qing
Golub, Elizabeth T.
Durkin, Helen G.
Greenblatt, Ruth M.
Herold, Betsy C.
Nowicki, Marek J.
Kassaye, Seble
Cho, Michael W.
Pinter, Abraham
Landay, Alan L.
Mestecky, Jiri
Kozlowski, Pamela A.
Differences in serum IgA responses to HIV-1 gp41 in elite controllers compared to viral suppressors on highly active antiretroviral therapy
title Differences in serum IgA responses to HIV-1 gp41 in elite controllers compared to viral suppressors on highly active antiretroviral therapy
title_full Differences in serum IgA responses to HIV-1 gp41 in elite controllers compared to viral suppressors on highly active antiretroviral therapy
title_fullStr Differences in serum IgA responses to HIV-1 gp41 in elite controllers compared to viral suppressors on highly active antiretroviral therapy
title_full_unstemmed Differences in serum IgA responses to HIV-1 gp41 in elite controllers compared to viral suppressors on highly active antiretroviral therapy
title_short Differences in serum IgA responses to HIV-1 gp41 in elite controllers compared to viral suppressors on highly active antiretroviral therapy
title_sort differences in serum iga responses to hiv-1 gp41 in elite controllers compared to viral suppressors on highly active antiretroviral therapy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495342/
https://www.ncbi.nlm.nih.gov/pubmed/28671952
http://dx.doi.org/10.1371/journal.pone.0180245
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