HIV X4 Variants Increase Arachidonate 5-Lipoxygenase in the Pulmonary Microenvironment and are associated with Pulmonary Arterial Hypertension
| Autor: | Deborah Molehin, Bum-Yong Kang, Justin M. Smith, Sonia C. Flores, Laurence Huang, Roy L. Sutliff, Cari F. Kessing, Kevin Pruitt, Edgar G. Martinez, Edu B Suárez-Martínez, Bryan McNair, Kaiser M. Bijli, Sushma K. Cribbs, Laura Pumarejo-Gomez, Priscilla Y. Hsue, Brandy E. Wade, Sharilyn Almodovar, David M. Guidot, Kristi M. Porter, William R. Tyor, Ethan A. Salazar, Robert Alexis Lopez-Astacio, Jaritza Perez Hernandez |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male viruses lcsh:Medicine HIV Infections Pathogenesis 030204 cardiovascular system & hematology HIV Envelope Protein gp120 CXCR4 Transgenic Cohort Studies Chemokine receptor 0302 clinical medicine Receptors 2.1 Biological and endogenous factors lcsh:Science Lung Cells Cultured Inbred F344 Leukotriene Pulmonary Arterial Hypertension Cultured Multidisciplinary medicine.diagnostic_test biology Molecular medicine virus diseases Middle Aged Infectious Diseases medicine.anatomical_structure Phenotype Arachidonate 5-lipoxygenase HIV/AIDS Female Rats Transgenic Infection Biotechnology Adult Receptors CXCR4 Genotype Anti-HIV Agents Cells Pulmonary Artery Article 03 medical and health sciences Genetics medicine Animals Humans Tropism Arachidonate 5-Lipoxygenase Animal business.industry lcsh:R Endothelial Cells Rats Inbred F344 Rats Disease Models Animal Viral Tropism 030104 developmental biology Bronchoalveolar lavage Disease Models Immunology biology.protein HIV-1 lcsh:Q business |
| Zdroj: | Scientific Reports Scientific reports, vol 10, iss 1 Scientific Reports, Vol 10, Iss 1, Pp 1-15 (2020) |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|