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HIV X4 Variants Increase Arachidonate 5-Lipoxygenase in the Pulmonary Microenvironment and are associated with Pulmonary Arterial Hypertension
Pulmonary Arterial Hypertension (PAH) is overrepresented in People Living with Human Immunodeficiency Virus (PLWH). HIV protein gp120 plays a key role in the pathogenesis of HIV-PAH. Genetic changes in HIV gp120 determine viral interactions with chemokine receptors; specifically, HIV-X4 viruses inte...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366722/ https://www.ncbi.nlm.nih.gov/pubmed/32678115 http://dx.doi.org/10.1038/s41598-020-68060-9 |
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author | Almodovar, Sharilyn Wade, Brandy E. Porter, Kristi M. Smith, Justin M. Lopez-Astacio, Robert A. Bijli, Kaiser Kang, Bum-Yong Cribbs, Sushma K. Guidot, David M. Molehin, Deborah McNair, Bryan K. Pumarejo-Gomez, Laura Perez Hernandez, Jaritza Salazar, Ethan A. Martinez, Edgar G. Huang, Laurence Kessing, Cari F. Suarez-Martinez, Edu B. Pruitt, Kevin Hsue, Priscilla Y. Tyor, William R. Flores, Sonia C. Sutliff, Roy L. |
author_facet | Almodovar, Sharilyn Wade, Brandy E. Porter, Kristi M. Smith, Justin M. Lopez-Astacio, Robert A. Bijli, Kaiser Kang, Bum-Yong Cribbs, Sushma K. Guidot, David M. Molehin, Deborah McNair, Bryan K. Pumarejo-Gomez, Laura Perez Hernandez, Jaritza Salazar, Ethan A. Martinez, Edgar G. Huang, Laurence Kessing, Cari F. Suarez-Martinez, Edu B. Pruitt, Kevin Hsue, Priscilla Y. Tyor, William R. Flores, Sonia C. Sutliff, Roy L. |
author_sort | Almodovar, Sharilyn |
collection | PubMed |
description | Pulmonary Arterial Hypertension (PAH) is overrepresented in People Living with Human Immunodeficiency Virus (PLWH). HIV protein gp120 plays a key role in the pathogenesis of HIV-PAH. Genetic changes in HIV gp120 determine viral interactions with chemokine receptors; specifically, HIV-X4 viruses interact with CXCR4 while HIV-R5 interact with CCR5 co-receptors. Herein, we leveraged banked samples from patients enrolled in the NIH Lung HIV studies and used bioinformatic analyses to investigate whether signature sequences in HIV-gp120 that predict tropism also predict PAH. Further biological assays were conducted in pulmonary endothelial cells in vitro and in HIV-transgenic rats. We found that significantly more persons living with HIV-PAH harbor HIV-X4 variants. Multiple HIV models showed that recombinant gp120-X4 as well as infectious HIV-X4 remarkably increase arachidonate 5-lipoxygenase (ALOX5) expression. ALOX5 is essential for the production of leukotrienes; we confirmed that leukotriene levels are increased in bronchoalveolar lavage fluid of HIV-infected patients. This is the first report associating HIV-gp120 genotype to a pulmonary disease phenotype, as we uncovered X4 viruses as potential agents in the pathophysiology of HIV-PAH. Altogether, our results allude to the supplementation of antiretroviral therapy with ALOX5 antagonists to rescue patients with HIV-X4 variants from fatal PAH. |
format | Online Article Text |
id | pubmed-7366722 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-73667222020-07-17 HIV X4 Variants Increase Arachidonate 5-Lipoxygenase in the Pulmonary Microenvironment and are associated with Pulmonary Arterial Hypertension Almodovar, Sharilyn Wade, Brandy E. Porter, Kristi M. Smith, Justin M. Lopez-Astacio, Robert A. Bijli, Kaiser Kang, Bum-Yong Cribbs, Sushma K. Guidot, David M. Molehin, Deborah McNair, Bryan K. Pumarejo-Gomez, Laura Perez Hernandez, Jaritza Salazar, Ethan A. Martinez, Edgar G. Huang, Laurence Kessing, Cari F. Suarez-Martinez, Edu B. Pruitt, Kevin Hsue, Priscilla Y. Tyor, William R. Flores, Sonia C. Sutliff, Roy L. Sci Rep Article Pulmonary Arterial Hypertension (PAH) is overrepresented in People Living with Human Immunodeficiency Virus (PLWH). HIV protein gp120 plays a key role in the pathogenesis of HIV-PAH. Genetic changes in HIV gp120 determine viral interactions with chemokine receptors; specifically, HIV-X4 viruses interact with CXCR4 while HIV-R5 interact with CCR5 co-receptors. Herein, we leveraged banked samples from patients enrolled in the NIH Lung HIV studies and used bioinformatic analyses to investigate whether signature sequences in HIV-gp120 that predict tropism also predict PAH. Further biological assays were conducted in pulmonary endothelial cells in vitro and in HIV-transgenic rats. We found that significantly more persons living with HIV-PAH harbor HIV-X4 variants. Multiple HIV models showed that recombinant gp120-X4 as well as infectious HIV-X4 remarkably increase arachidonate 5-lipoxygenase (ALOX5) expression. ALOX5 is essential for the production of leukotrienes; we confirmed that leukotriene levels are increased in bronchoalveolar lavage fluid of HIV-infected patients. This is the first report associating HIV-gp120 genotype to a pulmonary disease phenotype, as we uncovered X4 viruses as potential agents in the pathophysiology of HIV-PAH. Altogether, our results allude to the supplementation of antiretroviral therapy with ALOX5 antagonists to rescue patients with HIV-X4 variants from fatal PAH. Nature Publishing Group UK 2020-07-16 /pmc/articles/PMC7366722/ /pubmed/32678115 http://dx.doi.org/10.1038/s41598-020-68060-9 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Almodovar, Sharilyn Wade, Brandy E. Porter, Kristi M. Smith, Justin M. Lopez-Astacio, Robert A. Bijli, Kaiser Kang, Bum-Yong Cribbs, Sushma K. Guidot, David M. Molehin, Deborah McNair, Bryan K. Pumarejo-Gomez, Laura Perez Hernandez, Jaritza Salazar, Ethan A. Martinez, Edgar G. Huang, Laurence Kessing, Cari F. Suarez-Martinez, Edu B. Pruitt, Kevin Hsue, Priscilla Y. Tyor, William R. Flores, Sonia C. Sutliff, Roy L. HIV X4 Variants Increase Arachidonate 5-Lipoxygenase in the Pulmonary Microenvironment and are associated with Pulmonary Arterial Hypertension |
title | HIV X4 Variants Increase Arachidonate 5-Lipoxygenase in the Pulmonary Microenvironment and are associated with Pulmonary Arterial Hypertension |
title_full | HIV X4 Variants Increase Arachidonate 5-Lipoxygenase in the Pulmonary Microenvironment and are associated with Pulmonary Arterial Hypertension |
title_fullStr | HIV X4 Variants Increase Arachidonate 5-Lipoxygenase in the Pulmonary Microenvironment and are associated with Pulmonary Arterial Hypertension |
title_full_unstemmed | HIV X4 Variants Increase Arachidonate 5-Lipoxygenase in the Pulmonary Microenvironment and are associated with Pulmonary Arterial Hypertension |
title_short | HIV X4 Variants Increase Arachidonate 5-Lipoxygenase in the Pulmonary Microenvironment and are associated with Pulmonary Arterial Hypertension |
title_sort | hiv x4 variants increase arachidonate 5-lipoxygenase in the pulmonary microenvironment and are associated with pulmonary arterial hypertension |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366722/ https://www.ncbi.nlm.nih.gov/pubmed/32678115 http://dx.doi.org/10.1038/s41598-020-68060-9 |
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