Mice with humanized immune system as novel models to study HIV-associated pulmonary hypertension

• Published in: Frontiers in immunology Vol. 13; p. 936164
• Main Authors: Rodriguez-Irizarry, Valerie J, Schneider, Alina C, Ahle, Daniel, Smith, Justin M, Suarez-Martinez, Edu B, Salazar, Ethan A, McDaniel Mims, Brianyell, Rasha, Fahmida, Moussa, Hanna, Moustaïd-Moussa, Naima, Pruitt, Kevin, Fonseca, Marcelo, Henriquez, Mauricio, Clauss, Matthias A, Grisham, Matthew B, Almodovar, Sharilyn
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 05-08-2022
• Subjects: Animals; EMAP II; HIV; HIV Infections - complications; HIV-associated pulmonary hypertension; HIV-PH; HIV-PH Pulmonary hypertension; Humans; Hypertension, Pulmonary - etiology; hypoxia; Hypoxia - pathology; Immune System - pathology; Immunology; Inflammation - complications; Mice; Pulmonary Arterial Hypertension; hypoxia; EMAP II; HIV; HIV-associated pulmonary hypertension; HIV-PH Pulmonary hypertension; HIV-PH; Humanized mice; SU5416
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.936164

People living with HIV and who receive antiretroviral therapy have a significantly improved lifespan, compared to the early days without therapy. Unfortunately, persisting viral replication in the lungs sustains chronic inflammation, which may cause pulmonary vascular dysfunction and ultimate life-threatening Pulmonary Hypertension (PH). The mechanisms involved in the progression of HIV and PH remain unclear. The study of HIV-PH is limited due to the lack of tractable animal models that recapitulate infection and pathobiological aspects of PH. On one hand, mice with humanized immune systems (hu-mice) are highly relevant to HIV research but their suitability for HIV-PH research deserves investigation. On another hand, the Hypoxia-Sugen is a well-established model for experimental PH that combines hypoxia with the VEGF antagonist SU5416. To test the suitability of hu-mice, we combined HIV with either SU5416 or hypoxia. Using right heart catheterization, we found that combining HIV+SU5416 exacerbated PH. HIV infection increases human pro-inflammatory cytokines in the lungs, compared to uninfected mice. Histopathological examinations showed pulmonary vascular inflammation with arterial muscularization in HIV-PH. We also found an increase in endothelial-monocyte activating polypeptide II (EMAP II) when combining HIV+SU5416. Therefore, combinations of HIV with SU5416 or hypoxia recapitulate PH in hu-mice, creating well-suited models for infectious mechanistic pulmonary vascular research in small animals.