HIV, atherosclerosis and inflammation: implications for treatment.

AuthorChan, William
PositionLEADING ARTICLE - Report


Atherosclerosis is characterised by a chronic inflammatory state with upregulation of many immunomodulatory paracrine, humoral and cellular factors along the inflamed dysfunctional vascular endothelium [1]. This inflammatory process ultimately results in formation of atherosclerotic plaques along the vascular tree, which are prone to atherothrombotic sequelae [2]. Although the acquired immunodeficiency syndrome is associated with profound immunosuppression, human immunodeficiency virus (HIV) infection in its early stages and immune reconstitution following highly active antiretroviral therapy (HAART) are more associated with chronic immune activation and dysregulation that may accelerate atherosclerosis already occurring in these patients. Beyond the deleterious chronic inflammatory effects of HIV infection, the adverse metabolic effects of HIV therapy and the disproportionately increased burden of traditional cardiovascular risk factors among these patients [3-5] may contribute to the increased incidence of atherosclerosis observed in this group [6]. This article highlights recent progress made in our understanding of the pathophysiology of atherosclerosis and cardiovascular disease (CVD) in HIV-infected patients, and also discusses potential therapeutic strategies in this group of patients.


In the pre-HAART era (before 1996), the cardiac manifestations of HIV were mainly due to the toxic and inflammatory effects of HIV and included cardiomyopathy, pancarditis and pulmonary hypertension leading to heart failure [7] (Table 1). However, even as early as 1992 autopsy case reports describing coronary lesions among HIV-infected patients began to appear [8,9]. Seminal cases of acute coronary syndromes in HIV-infected patients were first reported in 1998 [10] and histopathological analysis of atheromas suggested a distinctive form of diffuse atherosclerosis characterised by proliferation of smooth muscle cells, mixed with abundant elastic fibres, resulting in endoluminal protrusions [11].

The pathogenesis of atherosclerosis in HIV-infected patients remains speculative and is likely multifactorial in aetiology, as in the non-HIV setting (Figure 1). Case reports in the pre-HAART era suggested that HIV itself maybe pro-atherogenic, perhaps due to the increased systemic inflammatory response it perpetuates, as well as that caused by concomitant infections and endothelial injury [12,13]. We have recently described another mechanism by which HIV may contribute to foam cell formation by impairing cholesterol efflux [14]. However, most of the evidence linking HIV with accelerated atherosclerosis has emerged in the post-HAART era.

Although several observational studies have shown an association between lipodystrophy and HAART with the development of subclinical atherosclerosis in HIV-infected patients (independent of traditional cardiovascular risk factors) as detected by coronary calcium [15,16], other studies have not reported such an association [17].

Similarly, results from retrospective studies linking HAART with CVD have published conflicting results. Several studies [18] reported significant associations but the largest, of 36,766 patients who received care for HIV infection at Veterans Affairs facilities between January 1993 and June 2001, showed no increase in the rate of cardiovascular or cerebrovascular events or related mortality [19]. However, all these studies suffer from the inherent biases of retrospective studies, including the lack of a control group.

Most prospective studies have reported a significant, albeit small, increased risk in development of CVD with HAART. Friis-Moller and colleagues from the DAD study group reported a 26% relative increase in the rate of myocardial infarction per year of exposure to HAART during the first 4-6 years of use but the absolute risk was low and should be balanced against the benefits of antiretroviral treatment [20]. This risk seems to be driven by increased exposure to protease inhibitors (PIs), which is partly explained by dyslipidaemia, rather than by concomitant non-nucleoside reverse transcriptase inhibitors (NNRTI) [3]. These findings have been corroborated in other studies [12,13,21,22].

Taken together, the weight of current evidence supports an increased risk of CVD among HIV-infected patients but this risk may be outweighed by the benefits gained from HAART as reported by SMART investigators [23]. Nevertheless, excess CVD (6-15% of all deaths in HIV-infected patients [24,25]) remains an important impediment to the health of people who are now living longer with HIV and improvements in our understanding of its pathophysiology will allow better treatment strategies to be devised for primary and secondary prevention purposes.


Probable key processes involved in the pathogenesis of atherosclerosis are depicted in Figure 1. Interest in atherosclerosis as a chronic immune-mediated inflammatory disease was stimulated by the realisation that C-reactive protein (CRP) was elevated in patients with unstable angina [26] and that it could predict future cardiovascular risk even among apparently healthy men and women [27,28]. Moreover, the most prominent T cell type in human atheromas is the CD4+ T cell of the Th1 subset [29,30], the same population infected by HIV. Th1 cells, like macrophages, recognise oxidised low density lipoprotein cholesterol (ox-LDL) and produce interferon (IFN)-[gamma] and tumour necrosis factor (TNF)-[alpha] to further recruit and activate monocytes and macrophages [31,32]. Both Th1 T cells and macrophages are known long-term reservoirs for HIV [33] and thus it is likely that Th1 T cell and macrophage cross-talk within the coronary circulation, in the presence of a dysfunctional endothelium, can contribute to atherogenesis (Figure 1). Below, we outline our current understanding of aetiopathogenic factors involved with atherosclerosis in HIV-infected patients.



High-sensitivity CRP (hsCRP) is an established biomarker of chronic inflammation produced by the liver in response to interleukin 6 (IL-6), a pro-inflammatory cytokine generated by the inflamed vasculature as well as by visceral adipose tissue in patients with the metabolic syndrome and established atherosclerosis [34-36] (Figure 1). Elevations in hsCRP and other pro-inflammatory cytokines (for example IL-1 and IL-6) occur in both atherosclerosis and HIV [37-39]. High CRP concentrations independently predicted an increased acute myocardial infarction risk in HIV-infected patients [5], correlated with the presence of traditional cardiovascular risk factors in HAART-treated patients [40], and were higher among patients receiving HAART [41]. Moreover, hsCRP may also provide further prognostic information for patients with HIV as hsCRP levels have been associated with HIV progression [42].

Whether CRP is merely a marker for vascular inflammation or if it does mediate various aspects of atherogenesis remains to be determined [43]. Mechanistically, CRP can promote LDL uptake in macrophages, stimulate LDL oxidation, and recruit more monocytes to the inflamed endothelium by increasing monocyte chemoattractant protein-1 (MCP-1) production [44]. However, clinical studies of CRP polymorphisms have failed to identify a positive association between genetically elevated CRP levels and raised cardiovascular risk [45,46]. What is not contentious, however, is that hsCRP is a robust marker for CVD risk stratification that needs to be validated in the HIV setting.

Interestingly, the stimuli driving chronic vascular inflammation in HIV have not yet been defined. Is it the HIV itself, HAART, the metabolic and anthropometric abnormalities in chronic HIV infection, traditional cardiovascular risk factors (Figure 2) or some as yet unidentified factor? It has been recently proposed that microbial translocation across the gut mucosa may be one of the causes of low-grade endotoxaemia that contributes to the chronic immune (monocyte) activation and inflammation in HIV-infected patients [47]. Monocytes in HIV-infected patients frequently express activation markers (CD38, CD69, CD11b, HLA-DR) [48-50] and secrete proinflammatory cytokines (e.g. IL-6). Despite prolonged HAART, immune activation has been reported to persist in chronically infected HIV patients suggesting that immune dysregulation (accelerated T cell activation and proliferation) and inflammation remain attractive culprits (and targets) to explain the elevation in CRP and other proinflammatory cytokines [51-54] that ultimately drive the atherosclerotic process in these patients.



Endothelial dysfunction, a likely precursor of early atherosclerosis, has been reported in HAART-naive patients and in patients treated with PIs and nucleoside reverse transcriptase inhibitors (NRTIs). The mechanisms for HIV-mediated endothelial dysfunction may be multiple and include HIV-1 envelope glycoprotein 120 upregulation of endothelial intercellular adhesion molecule-1 expression by endothelial cells [55]; HIV tat protein interaction with signal transduction pathways that lead to increased expression of adhesion molecules, vascular endothelial growth factors and platelet activating factor [56,57]; and HIV membrane microparticle...

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