HIV-Tat and vascular endothelium: implications in the HIV associated brain, heart, and lung complications

Abstract

Following the advent of antiretroviral therapy (ART), neurological, cardiovascular, and pulmonary comorbidities emerged as major challenges in treating non-infectious complications in people living with HIV. Despite effective ART, HIV viral proteins can persist in circulation even in individuals with negligible viral loads, potentially contributing to cellular and tissue-level stress, inflammation, and related health complications. Most of the HIV protein: Tat (Trans activator of Transcription), expressed in HIV-infected cells, is actively secreted and exerts its pathological effects on non-infected cells, particularly impacting the vascular endothelium. This review focuses on the role and the underlying mechanisms of HIV-Tat in promoting endothelial dysfunction across the cardiovascular, pulmonary, and brain vasculature. Additionally, we discuss how HIV-Tat interacts synergistically with drugs of abuse to exacerbate endothelial damage. Importantly, the vascular damage caused by Tat is not fully mitigated by HAART, necessitating further mechanistic investigations and targeted therapeutic interventions. Additionally, cessation of drug abuse is indispensable for improving clinical outcomes and restoring vascular health in people living with HIV.

Keywords: Tat; blood brain barrier; cardiovascular dysfunction; endothelium; pulmonary vascular remodeling.

Figure 1

HIV-Tat, expressed by actively or latently infected macrophages and T cells, is secreted into the extracellular environment and damages neighboring or far-off non-infected cells, leading to range of pathological molecular alterations. These mainly include 1) heightened pro-inflammatory signaling, characterized by upregulated TLR4/NFκB activity, 2) enhanced oxidative stress, primarily through the dysregulation of eNOS and SOD2 expression, 3) hyperproliferation of vascular endothelial cells by modulating the VEGF, PDGF-BB, Rho/Ras or Notch signaling pathways and 4) disruption of tight junction proteins in the endothelium.