**2.3. HIV-1-triggered damage of ECs**

**Figure 1.** HIV-1 capability to promote inflammation, dyslipidemia, and endothelial dysfunction through the activation

Monocytes, depending on the cytokine/chemokine stimulation, may differentiate into M1 macrophages, which promote inflammation or into M2 macrophages, which are inflammatory resolving cells [19]. In particular, IFN-γ and IL-1β drive monocytes to acquire an M1 profile, whereas IL-4 and IL-13 generate M2 macrophages. HIV-1, by infecting macrophages, polarizes these cells toward the M1 phenotype [20]. This leads to the imbalance of the M1/M2

Endothelin-1 (ET-1) is a potent vasoconstrictor that promotes migration and proliferation of smooth muscle cells. HIV-1-triggered secretion of ET-1 promotes a reduction of vascular nitric oxide (NO) production by ECs with the consequent proliferation and migration of smooth

Altogether, these findings suggest that HIV-1 produces a general inflammatory microenvironment that contributes to dyslipidemia, EC dysfunction, chemotaxis, and vascular smooth muscle cell proliferation and migration. All these conditions are likely to foster endothelial

ratio, a condition necessary for sustaining endothelial dysfunction [21].

muscle cells leading to arterial vasoconstriction.

350 Endothelial Dysfunction - Old Concepts and New Challenges

degeneration and atherosclerotic plaque formation (**Figure 1**).

of different immune cells such as T and B cells, macrophages, and natural killer cells (NK cells).

HIV-1 is not an endothelium-tropic virus. It displays a narrow tropism predominantly determined by the cell surface receptors required for HIV-1 infection. CD4 and co-receptors are usually essential for HIV-1 to infect cells efficiently. The chemokine (C-C motif) receptor type 5 (CCR5) is the main co-receptor used in vivo, but variants that use another co-receptor, namely, chemokine (C-X-C motif) receptor type 4 (CXCR4), evolve during disease. In vitro, more than a dozen different co-receptors have been identified that support infection of cell lines by different HIV-1 strains. Moreover, HIV-1 particles interact with a range of cell surface receptors via interactions of its envelope glycoprotein gp120 with glycolipid galactocerebroside (gal)-C and its sulfated derivative.

HIV-1 capability to infect ECs in vitro depends on the tissue source of ECs and on their functional status. Microvascular ECs from the brain, kidney glomeruli, hepatic sinusoid, and bone marrow may be infected by HIV-1 in the absence of cytolysis [22, 23]. HIV-1 infection of brain ECs has been largely studied for its relevance in neurological diseases. T cell tropic but not brain-derived macrophage tropic HIV-1 strains selectively infect the brain endothelium in vitro, suggesting that T cell tropism may be important for HIV-1 entry through the bloodbrain barrier [22] and spreading in the central nervous system [24]. However, it is important to underline that in vivo studies do not support the presence of replicating virus in ECs. Even if HIV-1 infection of ECs cannot be completely ruled out, this may suggest an indirect action of molecules released in the microenvironment by HIV-1-infected cells at the base of the mechanism for vascular dysfunction.

In the pathophysiology of cardiovascular disease, the damage of ECs assessed by responses to altered blood flow (e.g., flow-mediated dilatation) and differences in the levels of EC specific molecules released in the blood (e.g., von Willebrand factor) represent a hallmark. The equilibrium between the mechanisms of vascular damage and repair plays a crucial role during homeostasis of vascular integrity. Following a blood vessel injury, high levels of circulating ECs (cECs) and microvesicles are released from endothelium, and the reinstatement of the vascular integrity mainly implies activity of endothelial progenitor cells (EPCs), plaque neovascularization, and reverse cholesterol transport [25]. EPCs are key determinants of endothelial dysfunction and show a high predictive value of early vascular disease. Interestingly, all vascular repair mechanisms are impaired in HIV<sup>+</sup> individuals who have lower EPC levels than HIV-1-seronegative subjects [26]. Decrease in the number of EPCs is attributed to HIV-1, which seems to be able to infect these cells because of their chemokine receptor CCR5 and CXCR4 expressions.

Along with reduced EPC levels, HIV<sup>+</sup> individuals show high plasma levels of EC-derived microvesicles also known as microparticles that are small membranous structures released from ECs during apoptosis, which impair the restoration of physiological conditions and sustain endothelial dysfunction [27]. HIV<sup>+</sup> patients also exhibit high plasma concentrations of high sensitivity C-reactive protein (hsCRP), IL-6, TNF-α, D-dimer, fibrinogen, soluble ICAM, and VCAM, suggesting endothelial activation and damage. These molecules are also responsible for an increased interaction of infected monocytes with ECs, thereby disrupting the integrity of the EC monolayer and promoting extravasation of HIV-1-infected cells into peripheral tissues and viral dissemination [28].
