Longitudinal Evaluation of Pulmonary Arterial Hypertension in a Rhesus Macaque (<i>Macaca mulatta</i>) Model of HIV Infection

Tarantelli, Rebecca; Schweitzer, Finja; Simon, Marc A.; Vanderpool, Rebecca; Christman, Ian; Rayens, Emily; Kling, Heather M.; Zullo, T.A; Carney, Jonathan; Lopresti, Brian J.; Bertero, Thomas; Chan, Stephen Y.; Norris, Karen A.

doi:10.30802/aalas-cm-18-000012

Cited by 11 publications

(24 citation statements)

References 38 publications

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“…Several plasma proinflammatory cytokine levels were increased during the course of SIV infection, including IL-6 and TNF-a 48 but there was no difference in levels of these cytokines between PAH+ and PAH-animals. Likewise, monocyte-associated chemokines MCP-1/CCL2 ( p = .0002), MDC/CCL22 ( p = .03), and IP-10/CXCL10 ( p = .002) increased during chronic SIV infection (Fig.…”

Section: Siv-infection Induces a Proinflammatory Plasma And Balf Envimentioning

confidence: 88%

“…46,47 In this model, clinical parameters, including peak VL, viral set points or plasma CD4+ T cell nadir were not predictive of the development or severity of SIV-PAH. 15,48 These findings do not exclude the possibility that specific viral proteins play a role in the pathogenesis; however, the lack of an association among VL, level of inflammation, and incidence or severity of HIV-PAH supports the hypothesis that secondary factors such as genetic factors or host-specific responses to viral infection may alter the disease progression.…”

Section: Figmentioning

confidence: 93%

“…Right heart catheterizations were performed on sedated animals at BL, 6 mpi, and before study termination (10-12 mpi), as previously described 15,48 using a Swan-Ganz balloon wedge pressure catheter advanced through the right atrium, right ventricle, and the pulmonary artery. Pressures were recorded with a Biopac M100 Acquisition system (Biopac, Goleta, CA).…”

Section: Right Heart Catheterizationmentioning

confidence: 99%

“…In instances for which we were unable to directly access pulmonary artery, mPAP was calculated as described by Peacock and colleagues 58 and validated for rhesus macaques. 48 Data were not obtained for one animal at 6 mpi and two at study termination. Anti-CD68 antibodies were used in conjunction with antibodies to phosphorylated STAT1, STAT3, and STAT6 to distinguish between three different macrophage populations.…”

Section: Right Heart Catheterizationmentioning

confidence: 99%

“…In a prospective study in rhesus macaques, we have shown that SIV-PAH developed between 6 and 12 months post-SIV infection in approximately 52% of the infected animals, however, we found no evidence that SIV infection severity, as measured by VL and CD4+ T cell levels, directly contributed to the susceptibility or severity of SIV-PAH. 48 Thus, we hypothesize that indirect effects, such as chronic inflammation, may promote the progression of SIV-PAH, and that monocytes and macrophages are central regulators of the pathogenic process. In this study, we investigated inflammatory mediators and phenotypic changes in monocytes and alveolar macrophages as driving forces or protective measures in SIV-PAH.…”

Section: Introductionmentioning

confidence: 99%

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

Schweitzer

Tarantelli

Rayens

et al. 2019

AIDS Research and Human Retroviruses

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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.

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Section: Siv-infection Induces a Proinflammatory Plasma And Balf Envimentioning

confidence: 88%

Section: Figmentioning

confidence: 93%

Section: Right Heart Catheterizationmentioning

confidence: 99%

Section: Right Heart Catheterizationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Schweitzer

Tarantelli

Rayens

et al. 2019

AIDS Research and Human Retroviruses

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NHLBI-CMREF Workshop Report on Pulmonary Vascular Disease Classification

Oldham

Hemnes

Aldred

et al. 2021

Journal of the American College of Cardiology

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Statin treatment prevents the development of pulmonary arterial hypertension in a nonhuman primate model of HIV-associated PAH

Rabacal

Schweitzer

Rayens

et al. 2019

Sci Rep

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Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by pulmonary vascular remodeling, elevated pulmonary arterial pressure, and right heart failure. Human immunodeficiency virus (HIV)-infected individuals have a higher incidence of PAH than the non-HIV infected population and evidence suggests a role for systemic and pulmonary inflammation in the pathogenesis of HIV-associated PAH. Due to their pleiotropic effects, including immune-modulatory and anti-inflammatory effects, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been considered for the treatment of PAH, with conflicting results. The effects of statins on HIV-associated PAH have not been specifically evaluated. We have developed a non-human primate (NHP) model of HIV-associated PAH that closely mimics HIV-PAH using simian immunodeficiency virus (SIV)-infected rhesus macaques (Macaca mulatta). We determined that treatment of healthy macaques with atorvastatin prior to and throughout SIV infection prevented the development of SIV-associated PAH. Additionally, SIV-infected macaques that initiated atorvastatin treatment during the early chronic disease stage had reduced incidence of PAH compared to untreated animals. Statin treatment reduced inflammatory mediators TGF-β, MIP-1α, and TNF-α and the numbers of CD14dimCD16+ non-classical monocytes, and CD14+CCR7−CD163−CD206+ alveolar macrophages previously shown to be associated with SIV-PAH. These results support the concept that statins reduce inflammatory processes that contribute to PAH and may provide a safe and effective prophylactic strategy for the prevention of PAH in HIV-infected individuals.

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Longitudinal Evaluation of Pulmonary Arterial Hypertension in a Rhesus Macaque (Macaca mulatta) Model of HIV Infection

Cited by 11 publications

References 38 publications

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

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

NHLBI-CMREF Workshop Report on Pulmonary Vascular Disease Classification

Statin treatment prevents the development of pulmonary arterial hypertension in a nonhuman primate model of HIV-associated PAH

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