Monocyte and Alveolar Macrophage Skewing Is Associated with the Development of Pulmonary Arterial Hypertension in a Primate Model of HIV Infection.

We investigated the relationship of monocytes, alveolar, and tissue-resident macrophage populations and the development of pulmonary arterial hypertension (PAH) in a nonhuman primate model of HIV infection. A prospective study of simian immunodeficiency virus-associated pulmonary arterial hypertension (SIV-PAH) was done. Rhesus macaques (n = 21) were infected with SIV. Blood, bronchoalveolar lavage fluid (BALF), and lung tissue were analyzed for monocyte and macrophage phenotypes and inflammatory mediators. Serial right heart catheterizations were performed at three time points throughout the study to assess hemodynamic alterations and the development of PAH. All 21 animals showed similar courses of SIV infection with an increasing proinflammatory plasma environment. At 6 months postinfection (mpi), 11 of 21 animals developed SIV-PAH (mPAP ≤25 mmHg; right ventricular systolic pressure [RVSP] ≤36 mmHg). PAH+ animals had an increased frequency of proinflammatory, nonclassical monocytes (CD14dimCD16+) (p = .06) in the peripheral blood and CD14+CCR7-CD163-CD206+ macrophages (p = .04) in BALF compared with PAH- animals at 6 mpi. Increased frequencies of these monocyte and macrophage phenotypes correlated with elevated RVSP (p = .04; p = .03). In addition, PAH+ animals had greater frequencies of tissue resident inflammatory M1-like CD68+STAT1+ (p = .001) and M2a-like CD68+STAT3+ macrophages (p = .003) and a lower frequency of anti-inflammatory M2c-like CD68+STAT6+ macrophages (p = .003) as well as fewer interleukin (IL)-10+ cells (p = .01). The results suggest that HIV-PAH is associated with skewing of monocytes and alveolar macrophages toward a proinflammatory, profibrotic phenotype. Furthermore, PAH+ animals may have diminished capacity to downregulate exaggerated chronic inflammation, as indicated by lower levels of IL-10 in PAH+ animals, contributing to disease progression.