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

• DOI: 10.3389/fimmu.2022.936164
• Publication Date: 2022-08-05T21:30:33Z
• Authors: Valerie J. Rodrig...; Alina C. Schneider; Daniel Ahle; Justin M. Smith; Edu B. Suarez-Mar...; Ethan A. Salazar; Brianyell McDanie...; Fahmida Rasha; Hanna Moussa; Naima Moustaïd-Mo...; Kevin Pruitt; Marcelo Fonseca; Mauricio Henriquez; Matthias A. Clauss; Matthew B. Grisham; Sharilyn Almodovar
• Keywords: Inflammation; Pulmonary Arterial Hypertension; 0303 health sciences; hypoxia; HIV-PH Pulmonary hypertension; Hypertension, Pulmonary; Immunology; HIV; HIV Infections; RC581-607; SU5416; 3. Good health; Mice; 03 medical and health sciences; Humanized mice; Immune System; HIV-associated pulmonary hypertension; Animals; Humans; HIV-PH; Immunologic diseases. Allergy; Hypoxia; EMAP II

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.