An Outlook on the Etiopathogenesis of Pulmonary Hypertension in HIV

Abstract

Although overall survival rates of patients infected with human immunodeficiency virus (HIV) have been significantly improved by antiretroviral therapy (ART), chronic comorbidities associated with HIV result in a worsening quality of life. Pulmonary arterial hypertension (PAH) is the most prevalent comorbidity associated with HIV infection. Despite low viremia and a non-replicative state maintained by ART, few people develop PAH. Previous data from animal models and human pulmonary microvascular endothelial cells (HPMVECs) suggests a constellation of events occurring during the propagation of HIV-associated PAH (HIV-PAH). However, these studies have not successfully isolated HIV virions, HIV-DNA, protein 24 antigen (p24), or HIV-RNA from the pulmonary endothelial cells (ECs). It provides an insight into an ongoing inflammatory process that could be attributed to viral proteins. Several studies have demonstrated the role of viral proteins on vascular remodeling. A composite of chronic inflammatory changes mediated by cytokines and growth factors along with several inciting risk factors such as Hepatitis C virus (HCV) co-infection, genetic factors, male predominance, illegal drug usage, and duration of HIV infection have led to molecular changes that result in an initial phase of apoptosis followed by the formation of apoptotic resistant hyperproliferative ECs with altered phenotype. This study aims to identify the risk factors and mechanisms behind HIV-PAH pathobiology at the host-pathogen interface at the intracellular level.

Keywords: bmp-2; hhv-8; hiv gp120; hiv-hcv co-infection; hiv-nef; hiv-tat; inflammatory mediators; nadph; pulmonary arterial hypertension; ros.

Figure 1. illustrates the effect of HIV on host immune cells

HIV targets both the dendritic cells and alveolar macrophages, causing T-cell activation. This ultimately results in an increased influx of CD8 cells with depletion of CD4 cells, leading to T-cell exhaustion. There is also a shift from the Th1 subset to the Th2 subset, altering cytokine release. The infected alveolar macrophages result in impaired phagocytosis, the release of inflammatory cytokines, and dysregulated immune system [11]. Th: T helper cell; IL: interleukin; MIP-1: macrophage inflammatory protein-1; TNF-α: tumor necrosis factor-alpha, HIV: human immunodeficiency virus Image credit: Jaimee Jacob Palakeel

Figure 2. The role of Nef protein in the pathogenesis of HIV-PAH

VEGF: vascular endothelial growth factor; MIP-1: macrophage inflammatory protein-1; TNF-α: tumor necrosis factor-alpha; PI3K: phosphoinositide 3-kinases; AKT: serine/threonine kinase (protein kinase B or AKT) pathway; P: phosphorylation; A: activation; HIV: human immunodeficiency virus; PAH: pulmonary arterial hypertension; Nef: negative factor Image credit: Jaimee Jacob Palakeel

Figure 3. The effect of HIV-Tat protein and morphine on the pulmonary vasculature

HIV-Tat interacts with Tip60 protein, a histone acetyltransferase, preventing the phosphorylation of ATM kinases and caspase activation, and leading to anti-apoptosis [2]. It results in the upregulation of the VEGF receptor, ensuing angiogenesis [16]. Both Tat and morphine cause overexpression of NOX enzymes that induce oxidative stress [30] on the pulmonary ECs, resulting in smooth muscle migration, proliferation, and vascular remodeling [16,20]. Likewise, Tat protein inhibits the activity of DNA-PK cs, the DNA repair protein, leading to the accumulation of damaged DNA and oxidative stress [2] Tat: transactivator of transcription; Tip60: Tat interacting protein 60KDa; ATM: ataxia telangiectasia mutated; VEGF: vascular endothelial growth factor; NOX: NADPH oxidase enzyme; ECs: endothelial cells; DNA-PKcs: DNA protein kinase catalytic subunit; P: phosphorylation; HIV: human immunodeficiency virus Image credit: Jaimee Jacob Palakeel

Figure 4. The role of mi-RNA on vascular remodeling

PPAR-γ: peroxisome proliferator-activated receptor- γ; VEGF: vascular endothelial growth factor Image credit: Jaimee Jacob Palakeel.