Vascular endothelial dysfunction in the wake of HIV and ART

Abstract

Mounting evidence points to increased rates of cardiovascular disease (CVD) among people living with HIV/AIDS (PLWHA). Endothelial dysfunction (loss of endothelium-dependent vascular relaxation in response to provasodilatory stimuli) constitutes an early pathophysiological event in atherogenesis and CVD. Both HIV-1 infection and antiretroviral therapy (ART) are implicated in the development of endothelial dysfunction; however, conclusions are frequently drawn from associations shown in epidemiological studies. In this narrative review of mainly in vitro and animal studies, we report on the current understanding of how various HIV-1 proteins, HIV-1-induced proinflammatory cytokines and common antiretroviral drugs directly impact vascular endothelial cells. Proposed cellular mechanisms underlying the switch to a dysfunctional state are discussed, including oxidative stress, impaired expression and regulation of endothelial nitric oxide (NO) synthase (eNOS) and increased expression of vascular adhesion molecules. From the literature, it appears that increased reactive oxygen species (ROS) production, linked to decreased NO bioavailability and ensuing endothelial dysfunction, may be proposed as a putative final common pathway afflicting the vascular endothelium in PLWHA. The HIV-1-proteins Tat, Gp120 and Nef in particular, the proinflammatory cytokine, TNF-α, and the antiretroviral drugs Efavirenz and Lopinavir, most commonly postulated to be primary causal agents of endothelial dysfunction, are also discussed. We conclude that, despite existing evidence from basic research papers, a significant gap remains in terms of the exact underlying cellular mechanisms involved in HIV-1 and ART induced endothelial dysfunction. Bridging this gap could help pave the way for future strategies to prevent and treat early cardiovascular changes in PLWHA.

Nef-induced CCL2 Expression Contributes to HIV/SIV Brain Invasion and Neuronal Dysfunction

“…The findings summarized herein not only integrate well into the “Trojan horse” model that states that a cell infected with HIV/SIV enters the brain leading to a persistent infection and consequently HAND (139) but also add to this model the fact that the transfer of Nef by microvesicles into endothelial cells and the subsequent induction of CCL2, mimics a pathophysiological state of the brain to which monocytes are recruited normally. Nef, in combination with other HIV/SIV proteins and even anti-retroviral drugs, possibly work together more efficiently to enable a rapid entry of HIV/SIV-infected cells into the brain (140). This interplay presumably plays a general role in HIV-associated diseases (141).…”

Dietary nitrate improves skeletal muscle microvascular oxygenation in HIV-infected patients receiving highly active antiretroviral therapy: a randomised, double-blind, cross-over, placebo-controlled study

“…without exercise interference). Such an analysis is important given that HIV-infected individuals typically exhibit endothelial dysfunction, which is an early stage of a cardiovascular event (26,27) . This finding certainly merits further investigation.…”

“…Vascular dysfunction observed in HIV-1 patients seems to be associated with a reduced bioavailability of NOa decrease in NO production and/or increased NO inactivation (3) . Since NO may influence oxygen utilisation by the cells, oxygen delivery to the skeletal muscle as well as oxygen utilisation by the muscle cells in response to exercise may be compromised in HIV-1 patients, thereby explaining the physical impairment observed in these patients (4) .…”

HIV-1 Tat Protein Enters Dysfunctional Endothelial Cells via Integrins and Renders Them Permissive to Virus Replication

“…In this regard, HIV-infected individuals display a chronic systemic inflammation and high IL-1β, TNF-α or IFN -γ plasma levels, even when they are treated with the combination antiretroviral therapy (cART) which reduces Human Immunodeficiency Virus (HIV)-1 replication or infectivity [13][14][15][16]. Indeed, in HIV infection, endothelial cells are chronically activated, release vascular adhesion molecules and angiogenic factors, and undergo numerous additional changes characteristic of endothelial dysfunction, which, in turn, has been proposed to contribute to the increased incidence of cardiovascular diseases observed in the pre-ART and in the ART era, respectively [17][18][19][20]. Moreover, although mainly associated to cardiovascular diseases, endothelial dysfunction occurs in all the AIDS and non-AIDS-associated morbidities [21].…”