There were 39.4 million people who are living with human immunodeficiency virus (HIV) worldwide in 2004, of whom 4.9 million were newly infected. In the United States, over 1 million people are currently infected with HIV, and about 40,000 new cases are diagnosed each year. Acquired immune deficiency syndrome (AIDS) was responsible for the deaths of 16,000 in the US in 2004.1

Highly active antiretroviral therapy (HAART) has greatly reduced the risk of potential fatal opportunistic infections and thus has expanded the life span of these patients. Therefore, other possible causes of morbidity and mortality in the HIV-positive population have come to the forefront. In the past several years, several clinical studies have suggested that HIV-infected patients experience unexpectedly high rates of cardiovascular disease.2–5 Clearly, acute coronary syndromes, in particular, myocardial infarction, are among these potential causes of morbidity and mortality in the HIV-positive population.

The effects of many cardiovascular risk factors such as age, smoking, and hyperlipidemia on the incidence of coronary heart disease in the general population have been established. However, the pathogenic mechanisms of the increased incidence of HIV-associated vascular diseases are largely unknown. Thus, this important clinical problem is under active investigation. In this review, we focus on the recent advances in HIV-associated vascular disease and endothelial injury. Clinical investigations and possible mechanisms of atherosclerosis, pulmonary hypertension, and thrombosis in HIV-infected patients are discussed. Recent achievements in the molecular mechanism of HIV-associated endothelial injury including direct HIV infection, expression of cytokines and adhesion molecules apoptosis, and endothelial permeability are also discussed.

ATHEROSCLEROSIS

Clinical studies have suggested that HIV-infected patients experience unexpectedly high rates of atherosclerotic disease. Autopsy reports provided the first data suggesting an association between coronary artery disease and HIV infection. Atherosclerotic pathology occurred in the absence of traditional risk factors involving coronary, peripheral, and cerebral arteries in HIV-infected patients.6–11 In recent years, more and more clinical studies have indicated that people with HIV infection are epidemiologically at a significantly greater risk for coronary heart disease and myocardial infarction than uninfected people of the same age.2,3,12 A retrospective analysis in France reported that the incidence of coronary heart disease was between 5 and 5.5 per 1,000 person-years among HIV-infected people, which was at least a threefold increase over the incidence (1.52 per 1,000 person-years) in the general French male population.12 In another retrospective study of 28,513 HIV-infected people, HIV-infected men up to age 34 years and women up to age 44 years had a significantly higher incidence of cardiovascular disease than age-matched people without HIV infection (2.16–6.76 versus 1.53–2.47, P < 0.01).2 Furthermore, Klein et al. found that HIV-positive members of the Northern California Kaiser Permanente Medical Care Program, a large health maintenance organization, had a significantly higher rate of hospitalization for coronary heart disease than HIV-negative members (6.5 versus 3.8, P = 0.03) and that the rate of myocardial infarction was also greater (4.3 versus 2.9, P = 0.07).3

Many clinical ultrasound imaging studies have in fact shown an increased prevalence of subclinical atherosclerosis in patients receiving antiviral therapy.13–16 Several clinical studies further demonstrated the association of the increased prevalence of atherosclerosis with HAART.4,17–19 A study of 88,029 HIV patients in the French Hospital Database between 1996 and 199917 reported that the incidence of myocardial infarction is related to the duration of exposure to protease inhibitor (PI). Exposure to PIs was associated with a relative hazard rate for MI of 2.56 (95% confidence). The standardized morbidity rate of men exposed to PIs for 18 months, relative to the French general male population, was 0.8%, but it increased to 2.9% for men exposed to PIs for ≥ 30 months.17 In a prospective study by the HIV Outpatient Study (HOPS) for 5,672 HIV-positive patients (mean age = 42.6 years) from nine U.S. clinics, the incidence of MI was significantly increased in patients with PIs in a linear fashion.4 The Data Collection of Adverse Events Study (DAD) was a prospective observational study of 23,468 patients (median age = 39 years) from 11 cohorts in Europe, Australia, and the United States. The incidence of MI increased with increasing exposure to HAART, and the adjusted risk rate per year of exposure ranged from 0.32% for no HAART use to 2.93% for ≥ 6 years of HAART use.18 Because of the strong evidence from prospective, observational, and surrogate end point studies suggesting that HAART may be associated with an increased risk of cardiovascular events and that they may be related in part to dyslipidemia, the Infectious Disease Society of America (IDSA) and Adult AIDS Clinical Trials Group (AACTG) have updated their guidelines for the intensity of risk reduction therapy adjusted to the patient’s risk of developing cardiovascular disease in HIV-infected adults receiving antiretroviral therapy.19

HIV infection may also cause endothelial damage predisposing to atherosclerotic disease through its effect on triglyceride levels. The HIV infection itself is associated with dyslipidemia. Hypertriglyceridemia was well described in AIDS patients before the introduction of PI therapy and has been associated with elevations of circulating interferon-γ (IFN-γ).20

The antiviral therapy can cause hyperlipidemia, hyperglycemia, and central obesity.21 Cardiovascular risk is increased by these metabolic derangements, and premature atherosclerotic vascular disease may be the consequence. In addition, PIs such as ritonavir, indinavir, and amprenavir upregulate CD36, a scavenger receptor mediating cholesterol uptake in macrophages.22 Furthermore, PIs directly impair endothelium-dependent vasodilation, a marker of vascular damage preceding atherosclerotic changes.21

Inflammation induced by HIV contributes to the atherosclerotic formation. Bobryshev reported that immunohistochemical staining revealed significantly more HIV-1-infected dendritic cells in the atherosclerotic arteries than in the non-diseased segments, and he concluded that the accumulation of HIV-1 in dendritic cells in the arterial wall may influence the progression of atherosclerosis.23 Human immunodeficiency viral proteins may be able to affect smooth muscle cell (SMC) proliferation, which is a major event in vascular lesion formation; HIV gp120 was found to be a potent mitogen for rat SMCs in vitro.24 This effect seems to be mediated via gp120 sequences related to neuropeptide Y.24 Several mechanisms of HIV-induced endothelial injury or dysfunction described in the succeeding paragraphs may also contribute to the aggressive atherosclerosis formation in HIV infected patients.

THROMBOSIS

Many thromboembolic complications in HIV-infected patients have been described, among them, deep vein thrombosis (DVT), pulmonary embolism, thrombotic microangiopathy, and retinal venous thrombosis.25–30 Epidemiological studies with populations numbering from 60 to 42,935 showed that the occurrence of venous thromboembolic complications among HIV-infected people is twofold to tenfold higher than in healthy populations of comparable age.29,31–35 Furthermore, the development of venous thrombosis is found to be associated with the severity of HIV infection, with an incidence twice as high in AIDS patients as in simple HIV infection patients.36 Furthermore, a significantly higher incidence of thromboembolic events was observed in patients with low CD4 counts (< 200/mm3).28 Thromboembolic complications are also associated with HAART, with a dramatically increased incidence of venous thrombotic events from 0.19% before the introduction of PIs to 1.07% after the use of PIs.32

The pathogenesis of the increased risk of thrombosis in HIV-infected patients is not completely understood yet, but it is probably of a multifactorial nature. First of all, it might be related to a hypercoagulation state in HIV-infected patients.37 Many activated coagulation factors have been reported to be increased while anticoagulants are reduced or deficient in HIV-infected patients. For example, low levels of antithrombin (AT) were reported in HIV-infected patients with thrombosis.38 The prevalence of lupus anticoagulant in HIV infection has ranged as high as 70%.39 Anticardiolipin antibodies have been reported in 46%–90% of HIV-infected patients.40 Sugerman et al. have reported that acquired protein S deficiency is common in HIV-infected children (75%), significantly more prevalent in children with a CD4 count < 200/mm3.41 Decreased levels of protein C have also been detected in HIV-infected patients,42,43 and reduced protein S plasma levels and diminished activity were reported.44,45 Another physiological coagulation inhibitor, heparin cofactor II, has also been reported to be deficient in HIV infection. Other possible contributing factors are hypoalbuminemia-related fibrin polymerization defects, endothelial dysfunction, and abnormalities of the fibrinolytic system.39 Various markers of endothelial cell damage such as von Willebrand factor (vWF), soluble thrombomodulin (sTM), adhesion molecule E-selectin, tissue-type plasminogen activator (tPA), plasminogen activator inhibitor (PAI-1), fibronectin, angiotensin-converting enzyme (ACE), and endothelin have been shown to be increased in the course of HIV-1 infection.46–50 The secretion of tPA, (PAI-1), sTM, and vWF creates alterations in the coagulation cascade and could predispose to thrombosis. Furthermore, HIV gp120 could induce tissue factor expression in vascular SMCs, which may have potential effects on the arterial wall thrombogenicity.51

PULMONARY HYPERTENSION

Primary pulmonary hypertension, first described in hemophilic HIV-infected patients, occurs with a frequency of approximately 0.5% in patients with HIV infection, whereas the general yearly incidence is only approximately 1 per million people.52 Pulmonary hypertension in HIV infection showed plexogenic pulmonary arteriopathy in 95% of all cases,53 similar to the findings in immunocompetent patients. Antiretroviral therapy remains questionable in the treatment, even though the potential for slowing the progression of pulmonary hypertension or even causing its regression, has been observed.54,55

The pathogenesis of HIV-related pulmonary hypertension is not well understood. In vivo and in vitro studies show that HIV does not infect lung endothelial cells and HIV DNA, RNA, or p24 antigen could not be detected in the pulmonary vessels of patients with HIV-related pulmonary hypertension.56–58 It is possible, however, that HIV indirectly induces the development of pulmonary hypertension through increased production of inflammatory cytokines and chemokines by infected lymphocytes and alveolar macrophages.56–58 Endothelial dysfunction is central to the pathogenesis of pulmonary hypertension.59 Studies show that HIV and gp120 proteins can induce injury in lung endothelial cells.60 HIV may cause endothelial damage and mediator-related vasoconstriction through stimulation by the envelope gp120, including direct release and effects of endothelin-1 (vasoconstrictor), IL-6, and tumor necrosis factor (TNF)-α in the pulmonary arteries.55,61 Endothelin-1 levels are elevated in patients with pulmonary hypertension, and its plasma concentrations correlate with the severity of the disease.62 There is also increased expression of endothelin-1 in the vascular endothelium of patients with pulmonary hypertension, and this correlates with pulmonary vascular resistance.63,64 In vitro studies show that HIV gp120 stimulates the production of endothelin-1 in primary human lung endothelial cells,65,66 which further suggests that HIV and secreted viral proteins may play a role in the production of vasoconstrictors within the lung and contribute to the development of pulmonary hypertension.

CYTOKINES AND ADHESION MOLECULES

Inflammation and endothelial dysfunction play important roles in atherosclerosis formation. Adhesion molecules enabling leukocytes to communicate and adhere to endothelial cells are essential for immunological and inflammatory responses.

HIV infection is associated with the inflammatory activation in the vascular wall. Tumor necrosis factor-α is an inflammatory cytokine that is expressed in large amounts by HIV-infected macrophages and can activate endothelial cells and enhance leukocyte adhesion.67,68 A clinical study conducted by de Larrañaga et al. found that HIV-infected patients had significantly higher plasma levels of TNF-α and IL-6 than uninfected controls. These levels correlated with viral load.69 Wolf et al. found that the levels of VCAM-1, intercellular adhesion molecule-1 (ICAM-1), and vWF were higher in untreated patients with HIV infection than in HIV-negative blood-donor controls, and the levels decreased significantly in all subjects in the HIV infection group after 5–13 months of antiviral treatment.70 Nordoy et al. also found significantly higher levels of TNF-α and neopterin, as well as soluble adhesion molecules sICAM-1 and sVCAM-1 in their HIV-infected patients than in controls.71

HIV activation of inflammatory pathways was suggested to be a specific effect of the transactivator of transcription protein (Tat). Buonaguro et al. showed that transduction of the Tat gene into a monocyte cell line led to TNF-β production, and the same effect was observed on T-lymphocyte and epithelial cell lines.72 The Tat protein also induces synthesis of NF-κB and IL-6 in both lymphoblastoid and epithelial cells.73 Furthermore, Westendorp et al. found that the Tat protein amplified TNF-α–induced activation of NF-κB by suppressing the synthesis of Mn-dependent superoxide dismutase, thus exposing the cells to oxidative stress. This effect was seen in both HeLa cells transfected with the Tat gene and soluble Tat protein-treated HeLa cells and T cells.74 The HIV Tat not only activates mononuclear cells to secrete cytokines but also activates endothelial cells to express inflammatory cytokines and adhesion molecules and contributes to angiogenesis and the development of Kaposi’s sarcoma (KS).75,76 Hofman et al. found that Tat appeared to bind to Flk-1/KDR, a VEGF-A tyrosine kinase receptor, as well as to mediate angiogenesis.77 Further studies discovered that Tat protein activated endothelial cells by increasing the expressions of E-selectin, IL-6, and IL-8.78,79 Interleukin-6 is considered to be an acute phase cytokine and can increase endothelial cell permeability, whereas IL-8 is chemotactic to leukocytes and assists in inflammatory cell recruitment. The HIV-1 Tat protein activated human umbilical vein endothelial cell E-selectin expression via an NF-kB–dependent mechanism.80 Tat protein also induced monocyte chemoattractant protein-1 (MCP-1) expression in brain astrocytes81 and human lung microvascular endothelial cells.82 Increased MCP-1 expression resulted in monocyte transmigration across the endothelial cells. Dhawan et al. showed that the HIV Tat protein also induced VCAM-I, ICAM-I, and endothelial cell adhesion molecule-I in cultured vascular endothelial cells.83 Furthermore, monocytes infected with HIV showed increased adherence to vascular endothelial cell layers. Infected monocytes also secreted gelatinase into the culture medium, markedly disrupting the endothelial cell layers with which they were co-cultured.84 Later research showed that these effects could be largely mimicked by extracellular treatment with Tat protein.85 Extracellular treatment with Tat protein also increased monocytes’ migratory behavior and their ability to penetrate reconstituted extracellular membranes.86

Besides the effect of Tat protein, HIV gp120 also has several effects relevant to endothelial cell functions. Furthermore, HIV gp120 has been shown to induce monocytes to express proinflammatory cytokines, thus activating endothelial cells., and HIV gp120 protein was able to increase the expressions of prostaglandin E2 and IL-1 in monocytes with a dose-dependent manner.87 Both IL-1 and prostanoids have profound effects on endothelial adhesive processes.88,89 Bragardo et al. studied two types of events mediating T cell–endothelial adhesion interaction: dynamic adhesion mediated by selectins and static adhesion mediated by integrins. Their study showed that gp120 enhanced dynamic adhesion, which involved CD31, CD38, and CD49d.90 In addition, HIV gp120 alone could also quickly cause monocytes to adhere to endothelial cells.91 Stins et al. demonstrated that soluble gp120 increased expression of ICAM-1, VCAM-1, and IL-6 in human brain microvascular endothelial cells from children and increased monocyte transmigration across the monolayer in vitro. They further discovered that the effect was mediated via CD4 in endothelial cells.92 In a HIV-1 g120 transgenic mouse model, ICAM-1, VCAM-1, and substance P were highly expressed in brain vessel endothelial cells, and there was a significant correlation between substance P and ICAM-1 expression.93 Furthermore, gp120 was able to enhance the TNF-α–mediated activation of NF-κB in Jurkat cells accompanied by increased formation of reactive intermediates such as H2O2.94 Recently, we have demonstrated that both soluble and membrane associated gp120 on virus-like particles could induce ICAM-1 expression on several types of cultured human endothelial cells and then increased monocyte adhesions to the endothelial monolayer.95

Expression of the HIV Nef protein in macrophages induces expression of two chemokines, macrophage inflammatory proteins-1α and -1β.96 Later work showed that treating monocytes with soluble Nef induced a variety of inflammatory factors—not only macrophage inflammatory proteins-1α and -1β, but also IL-1β, IL-6, and TNF-α. Furthermore, this release of inflammatory factors correlated with activation of NF-κB.97

APOPTOSIS

HIV-1–induced CD4+ T cell apoptosis is a major mechanism of HIV pathogenesis.98 Furthermore, HIV-1 is able to induce apoptosis in other types of cells, including endothelial cells. The apoptosis of microvascular endothelial cells has been observed in the brain tissue of AIDS patients,99 and similar EC apoptosis was demonstrated in the brain tissue of macaque monkeys infected with simian immunodeficiency virus (SIV).100 In a HIV transgenic rat model infected with a HIV provirus with a functional deletion of gag and pol, endothelial cell apoptosis and microscopic hemorrhages were observed in the brain tissue.101

Several in vitro studies have reported that HIV-1 and gp120 can induce EC apoptosis. Soluble gp120 as well as virion- and cell membrane-associated gp120 are able to induce toxicity and apoptosis in human umbilical vein endothelial cells (HUVECs).102,103 The HIV gp120 protein is also toxic to human brain microvascular endothelial cells.104 and is able to alter the functional and molecular properties of the blood–brain barrier.105 Recently, Kanmogne et al. reported that HIV-1 gp120 protein directly induced apoptosis in primary human lung microvascular endothelial cells as determined by TUNEL assay, annexin-V staining, and DNA laddering. The gp120-induced lung endothelial cell injury was considered as a possible contributing factor in the development of HIV-associated pulmonary hypertension.66 A study to investigate the effect of antiviral drugs and HIV infection on endothelial damage indicated that HIV-1 and gp120, not antiviral drug (AZT), induced apoptosis of neonatal rat ventricular myocytes (NRVMs) and human coronary artery endothelial cells (HCAECs).106 Soluble gp120 can increase HUVEC apoptosis in a biphasic fashion suggesting that multiple cellular factors might be involved in the effect.103 The apoptotic effect was found to be mediated through two cell surface receptors (CCR5 and CXCR4) on HUVECs, and by protein kinase C activation.102 Further studies revealed that gp120 on cell membranes or on virion particles was an even more potent inducer of endothelial apoptosis than soluble gp120.103 Caspases played an important role in this process; the pretreatment of cells with a general caspase enzyme inhibitor decreased the extent of HUVEC apoptosis induced by gp120/160.107 In fact, caspase-3 was activated and the pro-apoptotic molecule Bax was increased by HUVECs following gp120/160 treatment.107 In addition, recombinant gp120 was observed to induce human lung microvascular endothelial cells (HLMEC) apoptosis.108

The HIV Tat protein has also been demonstrated to induce endothelial apoptosis. Kim et al. 109 reported that HIV-1 Tat induced apoptosis of human brain miscrovascular endothelial cells (HBMEC), as evidenced by changes in the cleavage of poly(A)DP-ribose polymerase, DNA laddering, and incorporation of fluorescein into the nicked chromosomal DNA (TUNEL assay). Park et al.108 reported that Tat induced apoptosis of primary microvascular endothelial cells of lung origin by a mechanism distinct from TNF secretion or the Fas pathway. Also, Tat treatment increased caspase 3 activity, but not caspase-9 activity. Tat-derived peptides were also able to induce endothelial apoptosis. Treatment with the Tat 21-40 or 23-34 peptides increased the percentage of apoptotic cells in HUVECs, and it blocked the anti-apoptotic effect of VEGF. The Tat 27–38 peptide produced a similar striking apoptotic effect, and the Tat 46–57 peptide alone induced a modest increase in annexin V staining, but it completely blocked VEGF-induced anti-apoptosis.110

ENDOTHELIAL PERMEABILITY

The normal endothelial cell layer constitutes a macromolecular barrier between the blood vessels and underlying tissues. Injury to the ECs and endothelial junction structures could increase endothelial permeability, which is one of the critical events in pathological conditions such as atherosclerosis, inflammation, and other vascular complications.

Approximately 20% of individuals with AIDS develop HIV encephalitis (HIVE), and 15% develop HIV-1–associated dementia (HAD) in the United States.111 Despite the initial drop as a result of HAART, the prevalence of both HIVE and HAD is again increasing as HIV-infected individuals are living longer.112–114 Human immunodeficiency virus enters the CNS early after the primary infection.115–117 Studies have suggested that this mechanism of viral entry into the brain is dependent on the transmigration of infected leukocytes across the blood–brain barrier (BBB) and into the CNS.81,118 The BBB is composed mainly of specialized ECs in contact with astrocytes, which are connected by tight junction proteins.119 Blood–brain barrier dysfunction is common in HIV-1–infected individuals and is implicated in the pathogenesis of HAD.120,121 Tight junction protein disruption has been detected in HIV encephalitic brain tissue.120,122 Dysfunction of brain endothelial cells caused by HIV-1 plays an important role in AIDS neuropathogenesis.123,124

In addition to the BBB dysfunction in HIV-associated diseases, other damage to endothelial cell functions related to membrane permeability has been reported. In HIV-associated ocular microangiopathic syndrome, both clinical and morphologic studies revealed endothelial permeability and vascular leakage in the ocular tissue from HIV-infected patients.125 Also, pathological observations in patients with HIV-associated pulmonary artery hypertension include lesions of the pulmonary endothelium and increased endothelial cell permeability.58,66,126

The mechanisms of HIV-associated endothelial permeability increase are under active investigation. In vitro studies have shown that HIV-1 gp120 elicited endothelial toxicity,104 leading to disruption and downregulation of TJPs in HBMECs.105 A recent study showed that HIV gp120 derived from the macrophage (CCR5)-tropic virus decreased BBB tightness, increased permeability in HBMECs, and enhanced monocyte migration across in vitro BBB models. In addition, HIV gp120 was observed to cause dysfunction of the BBB via protein kinase C (PKC) pathways and receptor-mediated [Ca2+] release.127

Furthermore, HIV Tat may also have the capability to affect endothelial permeability. Tat protein significantly increases HUVEC monolayer permeability in a dose-dependent manner.128,129 The blocking experiments suggest that tyrosine kinase and MAP kinase, but not protein kinase G pathways, may mediate Tat-induced endothelial permeability.129 The Tat protein has also been shown to increase endothelial permeability in animal models.128,130 Tat synergized with basic growth factor (bFGF) induced vascular permeability and edema in guinea pigs and nude mice after systemic or local injection of Tat and bFGF.130 Kim et al. reported that HIV-1 Tat not only induced apoptosis of HBMEC but also significantly increased HBMEC permeability, resulting in the irreversible loss of BBB integrity.109 Avraham et al. reported that Tat treatment stimulated cytoskeletal organization and increased focal adhesion assembly leading to changes in the migration of HBMECs. Tat also induced BBB permeability, as observed in the endothelial cells isolated from HIV-1 Tat transgenic mice.131 Our recent study showed that HIV PI ritonavir increased endothelial permeability, decreases levels of tight junction proteins, and increased superoxide anion production in human dermal microvascular endothelial cells. These effects may underlie the mechanism of HIV PI-associated cardiovascular complications.132

Cellular molecules secreted from HIV-infected cells likely play an important role in BBB impairment and the development of HAD.133,134 Elevated levels of chemokine CC chemokine ligand 2 (CCL2), CCL5, and CXCL10 have been detected in the brain and cerebrospinal fluid (CSF) of patients with HIVE and HAD,135–138 suggesting that glial cells and endothelial cells, major sources of chemokines, may play a key role in the recruitment of uninfected and HIV-infected leukocytes into the CNS. Using a tissue culture model of the human BBB, Eugenin et al. demonstrated that HIV infection of human leukocytes resulted in their increased transmigration across the BBB in response to the chemokine CCL2, as well as in disruption of the BBB, as evidenced by enhanced permeability, reduction of tight junction proteins, and expression of matrix metalloproteinases (MMP)-2 and MMP-9. When HIV-infected cells were added to the model, they did not transmigrate in the absence of CCL2, nor did this condition alter BBB integrity.133 In the brain tissue from individuals with HIV encephalitis, there was an accumulation of cleaved and soluble forms of the extracellular region of the platelet/endothelial cell adhesion molecule (PECAM-1), i.e., sPECAM-1. In addition, HIV-infected individuals had elevated levels of sPECAM-1 in their sera. In vitro study demonstrated that HIV-infected leukocytes, when treated with CCL2, shed sPECAM-1, suggesting a mechanism of extracellular PECAM-1 cleavage and release dependent on HIV infection and CCL2.134

SUMMARY

With increased life expectancy in HIV patients, the prevalence of HIV-associated cardiovascular complications involving endothelial injuries has greatly increased in recent years, and it is a significant clinical concern. Dyslipidemia and other metabolic changes in patients with HIV and those using HAART may contribute to increased cardiovascular risk. Many clinical and laboratory studies have found that HIV infection causes profound functional alterations of the endothelium. The virus and its viral proteins such as gp120, Tat, and Nef are able to induce expression of several adhesion molecules and inflammatory cytokines such as ICAM-1, VCAM-1, E-selectin, TNF-α, and IL-6. Leukocyte adherence to the endothelium is enhanced as the expression of these cell adhesion molecules increases. Elevated circulating levels of vWF, a glycoprotein facilitating platelet adhesion, synthesized in endothelial cells and inflammatory cells, are elevated and correlate to circulating levels of inflammatory cytokines. A hypercoagulable state is induced depending on plasma HIV load. In addition, HIV and its viral proteins can also induce endothelial apoptosis and increase endothelial permeability. These effects could significantly contribute to vascular disease formation. However, the molecular mechanisms underlying HIV-associated vascular diseases and endothelial injury are not completely understood. Future studies on the associated mechanism of HIV infection and cardiovascular disease, as well as endothelial dysfunction, may contribute to the development of preventive and therapeutic approaches to the treatment of patients with HIV-associated cardiovascular disease.