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.

Figure 1.

Infection of cynomolgus macaques with simian immunodeficiency virus–human immunodeficiency virus 89.6P (SHIV_89.6P) is associated with elevated right atrial, right ventricular, and pulmonary arterial pressures (Mann-Whitney test, P = 0.001, 0.042, and 0.001, respectively), but not pulmonary capillary wedge pressure (Mann-Whitney test, P = 0.274). Right heart catheterizations were performed in 19 macaques, at approximately 20 months after SHIV infection, and compared with four uninfected control animals.

Figure 2.

Right ventricle (RV) pressure waveform morphology is consistent with stiffening of the vasculature. Arrow indicates a loss of the gentle sloping of the shoulder during systole after peak right ventricular systolic contraction, consistent with increased vascular tone. RV, right ventricle; PA, pulmonary artery.

Figure 3.

Relative pulmonary vascular resistance (PVR, Woods units) is elevated in SHIV-infected macaques (n = 4) compared with uninfected macaques (n = 3; P = 0.02), with no significant difference in relative cardiac output (Q, blood flow [cm/s]; P = 0.51) (P = 0.51).

Figure 4.

Hemodynamic evaluation of simian immunodeficiency virus (SIV)–infected rhesus macaques (Monkey numbers R58, R67, R73, R80, R85; see Table E1 for infection details). (A) Pulmonary artery systolic pressure is significantly elevated in rhesus macaques (RM) by 3 months post-SIV infection (PI) compared with baseline, as determined by Doppler echocardiography (two-way ANOVA, P = 0.023). Right heart catheterizations were performed in four rhesus macaques at baseline (before infection) and approximately 8 months after infection (PI). (B) Infection with SIV_ΔB670 is associated with elevated right atrial and pulmonary artery pressure and pulmonary artery systolic pressure (paired t test, P = 0.006, 0.032, and 0.038, respectively), but not pulmonary capillary wedge pressure (P = 0.215). (C) No significant difference was evident in systemic blood pressure before and after SIV infection (two-way ANOVA, P = 0.903). mos, months.

Figure 5.

Quantitative evidence of vascular pruning on computed tomography scans. Quantitative analysis of cross-sectional area (CSA) of vessels was performed, and indicated significantly fewer small vessels (CSA < 5 mm²) in SHIV-infected macaques (n = 19) than in control animals (n = 10; t test, P = 0.041). No significant difference was evident in vessels measuring 5–10 mm² (t test, P = 0.450). %CSA, percentage of cross-sectional area; CSA_{<5 mm²}, vessels with cross-sectional area < 5 mm²; CSA_{5–10 mm²}, vessels with a cross-sectional area of 5–10 mm². *P = 0.04.

Figure 6.

Characteristic histopathology of SHIV-infected and SIV-infected macaque lung tissue. Hematoxylin and eosin stain (A, C, E, and G) and Masson trichrome stain (B, D, F, and H) of normal (A and B), SHIV-infected (C and D), and SIV-infected (E–H) macaque lung tissue. Arrows indicate neointimal thickening (C), medial hyperplasia (E), collagen deposition (F), and perivascular lymphocytic tissue (G).