**2. Endothelial dysfunction during HIV-1 infection**

Chronic inflammation contributes to many leading causes of death, and in particular cardiovascular events have emerged as a clinically significant issue and have become the matter of several studies. HIV-1 infection is characterized by altered immune responses leading to a generalized chronic inflammation and, in particular, to a pro-inflammatory status in the vascular endothelium fostering the development of cardiovascular diseases [1]. A strong correlation between high plasma HIV-1 RNA levels and signs of endothelial dysfunction is known [2], and subclinical signs of atherosclerosis have been found in asymptomatic HIV<sup>+</sup> young men with long-standing HIV-1 disease [3]. As the efficacy of combined antiretroviral therapy (cART) improves and patients live longer, the prevalence of cardiovascular diseases is increasing in HIV<sup>+</sup> individuals [4, 5]. Moreover, many antiretroviral drugs, particularly HIV-1 protease inhibitors, can cause dyslipidemia, thus contributing to the increased risk for endothelial dysfunction. The high risk of endothelial dysfunction persists even in new-generation antiretroviral drugs era, despite the fact that several adverse metabolic effects (e.g., insulin resistance, dyslipidemia, and hypertension) are abolished [6]. In light of these considerations, the following paragraphs consider three essential factors in the development and pathogenesis of endothelial dysfunction during the natural course of HIV-1 infection: (a) the ability of HIV-1 to promote inflammation, (b) the HIV-mediated damage of endothelium, and (c) the capability of HIV-1 structural and regulatory proteins of affecting EC function.

#### **2.1. HIV-1 and inflammatory microenvironment**

Chronic activation of the immune system is a peculiar feature of HIV-1 infection. Persistent activation of immune cells is known to gain an elevated pro-inflammatory cytokine/chemokine release contributing to the development of a chronically inflamed microenvironment. HIV-1 virus cycle is dominated by a local replication at the transmission site and in local lymphoid tissues and then dissemination. Virus expansion is associated with a dramatic depletion of memory CD4<sup>+</sup> T cells, particularly from gut-associated lymphoid tissues and with increased plasma levels of pro-inflammatory cytokines and chemokines. During the early phase of infection, a pro-inflammatory cytokine storm contributes to the control of viral replication but also to the early immunopathology of the infection and to the associated long-term consequences. Many cell types contribute to the release of different pro-inflammatory cytokines and chemokines during HIV-1 infection [7] such as interferon (IFN)-α, tumor necrosis factor (TNF)-α, INFγ, interleukin (IL)-1β, IL-10, interferon gamma-induced protein (IP)-10, IL-15, IL-8, IL-6, IL-18, and monocyte chemoattractant protein (MCP)-1 [8, 9]. Antiretroviral therapy usually controls and even abolishes HIV-1 replication, but does not completely recover immune dysfunction. Therefore, immune alteration and inflammation are common features of HIV<sup>+</sup> patients even under successful cART.
