Human Immunodeficiency Virus‐1 Transgene Expression Increases Pulmonary Vascular Resistance and Exacerbates Hypoxia‐Induced Pulmonary Hypertension Development

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary arterial resistance and vessel remodeling. Patients living with human immunodeficiency virus-1 (HIV-1) have an increased susceptibility to develop severe pulmonary hypertension (PH) irrespective of their CD4+ lymphocyte counts. While the underlying cause of HIV-PAH remains unknown, the interaction of HIV-1 proteins with the vascular endothelium may play a critical role in HIV-PAH development. Hypoxia promotes PH in experimental models and in humans, but the impact of HIV-1 proteins on hypoxia-induced pulmonary vascular dysfunction and PAH has not been examined. Therefore, we hypothesize that the presence of HIV-1 proteins and hypoxia synergistically augment the development of pulmonary vascular dysfunction and PH. We examined the effect of HIV-1 proteins on pulmonary vascular resistance by measuring pressure-volume relationships in isolated lungs from wild-type (WT) and HIV-1 Transgenic (Tg) rats. WT and HIV-1 Tg rats were exposed to 10% O2 for four weeks to induce experimental pulmonary hypertension to assess whether HIV-1 protein expression would impact the development of hypoxia-induced PH. Our results demonstrate that HIV-1 protein expression significantly increased pulmonary vascular resistance (PVR). HIV-1 Tg mice demonstrated exaggerated pulmonary vascular responses to hypoxia as evidenced by greater increases in right ventricular systolic pressures, right ventricular hypertrophy and vessel muscularization when compared to wild-type controls. This enhanced PH was associated with enhanced expression of HIF-1α and PCNA. In addition, in vitro studies reveal that medium from HIV-infected monocyte derived macrophages (MDM) potentiates hypoxia-induced pulmonary artery endothelial proliferation. These results indicate that the presence of HIV-1 proteins likely impact pulmonary vascular resistance and exacerbate hypoxia-induced PH.

Macrophage‐derived extracellular vesicles mediate smooth muscle hyperplasia: role of altered miRNA cargo in response to HIV infection and substance abuse

“…Increased survival of HIV-infected patients with the advent of antiretroviral therapy has resulted in an increase in the prevalence of noninfectious complications including pulmonary arterial hypertension (42–44). Furthermore, illicit drug use has been identified as one of the most common risk factors in the individuals with HIV-associated PAH (9, 10, 43).…”

Targeting mitochondrial reactive oxygen species to modulate hypoxia-induced pulmonary hypertension

“…However, neither MCAT nor SOD2 attenuated hypoxia-induced elevations in RVH. Numerous studies suggest that exposure to chronic hypoxia elevates RVSP which subsequently leads to elevated RVH [47, 48]. In contrast, we have previously observed that attenuation of hypoxia-induced RVSP reduces RVH [27] or has no effect on RVH [28].…”

Human Immunodeficiency Virus–Associated Pulmonary Arterial Hypertension

“…Additionally, Tat interacts with different types of receptors present on the surface of endothelial cells to induce VCAM-1 expression, p38 MAPK activation, nuclear factor-κB translocation, and increased expression of hypoxia-inducible factor-1α, which, collectively are involved in the pathogenesis of pulmonary vascular remodeling and dysfunction. 29 Tat may also bind VEGF and PDGF to increase local concentrations of these factors and this may explain the elevated levels of PDGF seen in lung biopsies of patients with HIV-associated PAH. 56 Similarly, elevated levels of PDGF have been found in patients with HIV infection and PAH, but not in HIV-infected individuals without PAH.…”

“…Increased levels of the cytokine interleukin (IL)-2 and the HIV-1 coreceptor CCR5 are also attributed to Tat. Exposure of isolated endothelial cells in culture to viral proteins (mainly Tat and gp120) results in the accumulation of hypoxia-inducible factor-1α protein 29 that occurs concomitant with increases in platelet-derived growth factor-B (PDGF-B). In turn, both hypoxia-inducible factor-1α and PDGF-B initiate and sustain activation of metabolic and proliferation by guest on May 11, 2018 http://circ.ahajournals.org/ Downloaded from signaling pathways that are contribute to pulmonary vascular remodeling in HIV.…”

“…29 The envelope glycoprotein 120 (gp120) is encoded by the HIV env gene, is exposed on the surface of the HIV virus, and facilitates entry of HIV into cells. With the support of coreceptors, such as CCR5 and CXCR4, gp120 is involved in the attachment of HIV to specific cell surface receptors, mainly CD4 + receptors.…”