Physiologic Changes in a Nonhuman Primate Model of HIV-Associated Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is increased in HIV, but its pathogenesis is not fully understood. Nonhuman primates infected with simian immunodeficiency virus (SIV) or SIV-HIV chimeric virus (SHIV) exhibit histologic changes characteristic of human PAH, but whether hemodynamic changes accompany this pathology is unknown. Repeated measurements of pulmonary artery pressures would permit longitudinal assessments of disease development and provide insights into pathogenesis. We tested the hypothesis that SIV-infected and SHIV-infected macaques develop physiologic manifestations of PAH. We performed right heart catheterizations, echocardiography, and computed tomography (CT) scans in macaques infected with either SIV (ΔB670) or SHIV (89.6P), and compared right heart and pulmonary artery pressures, as well as pulmonary vascular changes on CT scans, with those in uninfected control animals. Right atrial, right ventricular systolic, and pulmonary artery pressures (PAPs) were significantly elevated in 100% of macaques infected with either SIV or SHIV compared with control animals, with no difference in pulmonary capillary wedge pressure. PAPs increased as early as 3 months after SIV infection. Radiographic evidence of pulmonary vascular pruning was also found. Both SIV-infected and SHIV-infected macaques exhibited histologic changes in pulmonary arteries, predominantly consisting of intimal and medial hyperplasia. This report is the first to demonstrate SHIV-infected and SIV-infected macaques develop pulmonary hypertension at a high frequency, with physiologic changes occurring as early as 3 months after infection. These studies establish an important nonhuman primate model of HIV-associated PAH that will be useful in studies of disease pathogenesis and the efficacy of interventions.

Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension

“…Previously, a nonhuman primate model of HIV-induced PAH was described in rhesus macaques infected with SIV (23). Importantly, such a model replicates the hemodynamic and histologic manifestations of PAH.…”

Translating Research into Improved Patient Care in Pulmonary Arterial Hypertension

“…Moreover, confirmatory studies should ideally compare the efficacy of the tested molecule with current clinical therapies (47), because new drugs are likely to be given to patients with PAH who are already receiving standard PAH therapies. Finally, the use of preclinical larger-animal models more closely related to humans, such as pigs (51,52) or nonhuman primates (53), could result in increased clinical success rates of drugs in development. However, working with larger animals is extremely expensive and fraught with ethical concerns.…”

Human Immunodeficiency Virus–Associated Pulmonary Arterial Hypertension

“…Thus, the study of HIV-1 infection in these mice reconstituted with a human immune system makes this another optimal model for studying the mechanisms of HIV-1-induced immunopathobiology in the pulmonary vasculature. [21][22][23] In preclinical models, infection with either SIV or SHIV is associated with histopathologic changes in pulmonary arteries that are characteristic of human HIV-associated PAH. Thus, most knowledge pertaining to the pathogenesis of this disease was obtained initially from studying models infected with these viruses, even though the development of PAH in these models can be variable.…”

“…Thus, most knowledge pertaining to the pathogenesis of this disease was obtained initially from studying models infected with these viruses, even though the development of PAH in these models can be variable. 18,19,23 For example, Chalifoux and colleagues 24 studied 85 monkeys infected with SIV and observed that pulmonary blood vessels were affected adversely in 19 (22%), whereas the vasculature of other parenchymal organs was involved less frequently. As reported by other groups, 12,25,26 this pulmonary arteriopathy is characterized by abnormal pulmonary endothelial cells and plexiform lesions.…”

“…In contrast to SHIV-infected primates, the pulmonary vasculopathy observed in SHIVinfected mice lacks plexiform lesions or intimal fibrosis of the pulmonary arteries and is characterized mainly by vascular inflammation, which is also a component of PAH. 23,27 Many early attempts were made to localize HIV-1 in the lung as an explanation for the observed pulmonary vascular pathology. These efforts focused on identifying viral particles or any other evidence of immune complex deposition in the vascular endothelium using electron microscopy, immunohistochemistry, DNA in situ hybridization, and polymerase chain reaction; yet, all failed.…”