1. HIV X4 Variants Increase Arachidonate 5-Lipoxygenase in the Pulmonary Microenvironment and are associated with Pulmonary Arterial Hypertension
- Author
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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, and Jaritza Perez Hernandez
- Subjects
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 - Abstract
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.
- Published
- 2020