The DNA Damage Response and HIV-Associated Pulmonary Arterial Hypertension

Abstract

The HIV-infected population is at a dramatically increased risk of developing pulmonary arterial hypertension (PAH), a devastating and fatal cardiopulmonary disease that is rare amongst the general population. It is increasingly apparent that PAH is a disease with complex and heterogeneous cellular and molecular pathologies, and options for therapeutic intervention are limited, resulting in poor clinical outcomes for affected patients. A number of soluble HIV factors have been implicated in driving the cellular pathologies associated with PAH through perturbations of various signaling and regulatory networks of uninfected bystander cells in the pulmonary vasculature. While these mechanisms are likely numerous and multifaceted, the overlapping features of PAH cellular pathologies and the effects of viral factors on related cell types provide clues as to the potential mechanisms driving HIV-PAH etiology and progression. In this review, we discuss the link between the DNA damage response (DDR) signaling network, chronic HIV infection, and potential contributions to the development of pulmonary arterial hypertension in chronically HIV-infected individuals.

Can serum 8-hydroxy-2'-deoxyguanosine levels reflect the severity of pulmonary arterial hypertension?

“…PAH was defined as mean pulmonary artery pressure over 25 mmHg, pulmonary artery wedge pressure (PAWP) £15 mmHg, and PVR ³3 wood units. Considering the possible increase of oxidative DNA damage in chronic diseases, PAH subgroups associated with chronic diseases (i.e., connective tissue disease, HIV infection, and portal hypertension) and drug-toxin-associated PAH were not included in the study [5][6][7] . Other exclusion criteria were pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis, pulmonary hypertension (PH) due to left heart disease, PH due to lung diseases and/or hypoxia, chronic thromboembolic and/or other pulmonary artery obstructions with PH and PH with unclear or multifactorial mechanisms, history of chronic disease, abnormal renal function (creatinine >1.5 mg/dL), abnormal liver functions, acute infections, and neoplasia.…”

An Outlook on the Etiopathogenesis of Pulmonary Hypertension in HIV

“…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…”

“…HIV Tat HIV-transactivator of transcription (Tat) is a viral protein that is integral to HIV-1 transcription. Tat is secreted by the infected cells and taken up by healthy bystander cells through a cell-penetrating peptide within its core domain [ 2 , 3 ]. It is then trafficked to the nucleus, where the transcription elongation factor of the host is recruited to the transactivation response element (TAR) in the RNA, facilitating HIV-1 transcription [ 16 ].…”

“…Although antiretroviral therapy (ART) plays a significant role in reducing the viral load, improving CD4 levels, mitigating mortality rates, and prolonging life expectancy, people on treatment still face a worsening quality of life due to the chronic complications of the human Immunodeficiency virus (HIV) [1][2][3]. Pulmonary arterial hypertension (PAH) is the most prevalent life-threatening disease associated with HIV, leading to death.…”

“…Pulmonary arterial hypertension (PAH) is the most prevalent life-threatening disease associated with HIV, leading to death. PAH is defined as an elevated mean arterial pulmonary pressure of more than 25 mmHg with a pulmonary capillary wedge pressure of less than 15 mmHg and a pulmonary vascular resistance of more than 3 Wood units [ 2 , 4 ]. HIV-associated PAH (HIV-PAH) is categorized among group I classification of PAH with an overall prevalence about 0.5% higher than idiopathic PAH in the general population [ 4 , 5 ].…”