1. HIV X4 Variants Increase Arachidonate 5-Lipoxygenase in the Pulmonary Microenvironment and are associated with Pulmonary Arterial Hypertension.
- Author
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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, and Sutliff, Roy L
- Subjects
Lung ,Pulmonary Artery ,Cells ,Cultured ,Endothelial Cells ,Animals ,Rats ,Inbred F344 ,Humans ,Rats ,HIV-1 ,HIV Infections ,Disease Models ,Animal ,Arachidonate 5-Lipoxygenase ,Receptors ,CXCR4 ,HIV Envelope Protein gp120 ,Anti-HIV Agents ,Cohort Studies ,Genotype ,Phenotype ,Adult ,Middle Aged ,Female ,Male ,Rats ,Transgenic ,Viral Tropism ,Pulmonary Arterial Hypertension - 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