Coronary artery disease (CAD) is a leading long-term complication in HIV-positive individuals [1–3]. People with HIV infection have a 1.5-fold to two-fold increase in cardiovascular events compared with uninfected individuals [4–6], and HIV infection independently confers an odds ratio for acute myocardial infarction of approximately 2.07 after adjusting for traditional risk factors such as age, hypertension, diabetes and dyslipidemia . Such increase in the risk of CAD is largely owing to an increased risk of atherosclerosis. Consistent with the general model of atherosclerosis as an inflammatory disorder, the macrophage has been considered as the dominant intersection between HIV infection and increased risk of CAD . This view is substantiated by the direct effects of HIV on macrophage cholesterol metabolism and by macrophage recruitment at sites of chronic immune activation and inflammation caused by HIV-induced microbial translocation and low-grade endotoxemia . Dyslipidemia due to combined antiretroviral therapy (CART) further adds to the role of macrophages in atherosclerosis development in HIV-infected individuals [1,2]. Hence, the concept that HIV infection produces a proatherogenic phenotype in cells of the macrophage lineage.
The pathogenesis of CAD in HIV-positive individuals, however, might go beyond the damage to the macrophage compartment caused by HIV and/or CART. In the uninfected population, disturbance of endothelial cell function contributes significantly to the cardiovascular risk, and recent studies have shown that alterations in the number and function of circulating endothelial progenitor cells (EPCs) play an important role in CAD pathogenesis . Circulating EPCs are traditionally distinguished in (at least) two different subtypes, which are conventionally termed as colony-forming unit-endothelial cells (CFU-ECs) and endothelial colony-forming cells (ECFCs) [10–12]. CFU-ECs are of hematopoietic/monocytic origin, do not give rise directly to endothelial cells, but rather exert their angiogenic potential by localizing at sites of neoangiogenesis and by promoting the secretion in situ of important cytokines and growth factors, namely vascular endothelial growth factor among others [10–12]. The second type of circulating EPCs, that is the ECFC, do not possess hematopoietic markers, have a marked proliferative potential and may give rise to new vessels [10–13]. Although both CFU-EC and ECFC contribute to neoangiogenesis and revascularization at sites of endothelial damage, correlative studies have shown that low numbers of CFU-EC, rather than of ECFC, predict CAD in the general population [14,15]. This body of evidence points to circulating EPCs of either type as possible culprits for CAD development in HIV-infected individuals.
In this issue of the journal, Teofili et al. have investigated EPCs in HIV-positive patients. The working hypothesis of the authors is that HIV infection might impair the number and/or function of EPCs, thus contributing to endothelial dysfunction that plays a major role in determining the risk of CAD in the general population. In order to comprehensively address the different compartments of EPCs that are currently recognized in the bloodstream, both CFU-EC and ECFC were tested in CART-naive HIV-infected individuals and in sex-matched and age-matched normal controls . Importantly, the clinical history of all HIV-infected individuals was negative for cardiovascular diseases, dyslipidemia and thrombotic events. The fact that only CART-naive patients were included in the study is important in order to rule out any possible confounding effect directly related to the impact of CART on angiogenesis.
The main results of the study document that HIV infection favors the depletion of the CFU-EC subset of circulating EPCs . Compared with uninfected individuals, the number of circulating CFU-EC was significantly lower in HIV-positive patients. The other type of circulating EPCs, that is the ECFC compartment, was not affected by HIV . Consistently, a high load of proviral HIV-DNA was found in CFU-EC, but not in ECFC, indicating that CFU-ECs have a marked sensitivity to HIV infection . Such propensity to HIV infection may be accounted for by downregulation of apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like subunits, which was documented in this study . The fact that HIV disrupts the CFU-EC compartment, but leaves ECFC unaffected, is relevant in light of the observation that, in the general population, low numbers of CFU-EC, but not of ECFC, predict CAD [14,15].
The observation made by Teofili et al. that CFU-EC depletion is due to HIV itself and occurs before starting CART matches well with epidemiological data and with vascular imaging investigations of the HIV-infected population [1,3,17]. In fact, studies of carotid artery thickening, a surrogate marker of CAD, have shown that vessel thickness was up to 24% higher in HIV-infected individuals compared with uninfected sex-matched and age-matched persons and, importantly, was comparable in CART-naive patients and in those with virologic suppression on CART .
The work by Teofili et al. prompts several novel questions that are currently left unresolved by this and other studies. First, the abnormalities in circulating EPCs detected in CART-naive patients may undergo modifications upon starting CART therapy and after obtaining proper control of HIV replication. Different scenarios might be envisaged. If HIV is the dominant factor causing EPC disruption in infected individuals, then improvement of circulating EPC counts once HIV replication is under control would be expected. In an alternative scenario, however, CART, whose effects on the cardiovascular system are well known, might also have some effect on circulating EPCs, leading to a more serious damage of this compartment. Testing the effects of CART on EPC number and function might help understand better the cardiovascular toxicity of CART itself.
A second issue that is raised by the work of Teofili et al. concerns the true clinical relevance in vivo of the alterations of EPC number and function detected in vitro. In this respect, studies of large cohorts of HIV-infected individual aimed at correlating EPCs with CAD comorbidities before and after starting CART might provide interesting insights on the clinical effect of circulating EPCs abnormalities. From a technological standpoint, performing studies of circulating EPCs in large cohorts of patients might require a simplified version of the experimental strategy adopted in the study by Teofili et al., which might not be suitable for application in the multicentric setting. If a stringent clinical correlation emerged between alterations of circulating EPCs and CAD in correlative studies, the next step would be to test whether EPC alterations at the time of HIV infection and/or during follow-up might provide information for early prediction of CAD development.
A third question that is left unanswered is the involvement by HIV of the so-called residential EPCs, which reside in the artery walls and may have neoangiogenetic potential [9–13]. These cells were not investigated by Teofili et al., whose focus was on circulating, and not on residing, EPCs. The promising results documenting a disruption of the CFU-EC compartment in HIV-infected individuals, however, prompt further investigations aimed at assessing the status of other, newly identified EPCs subsets in this clinical context. These studies appear to be particularly important in a field, such as that of EPCs, that is rapidly evolving and is being continuously revisited, as documented by the strenuous efforts toward a more advanced classification of EPCs [18,19].
Since the introduction of CART, the interest in long-term complications of HIV infection and of its treatment has been rising steadily. The increase by several decades of the average life expectancy of HIV-positive individuals has revealed the emergence and the significant clinical impact of comorbidities that are caused by HIV infection itself and, in part, may be owing to several of the drugs contained in CART regimens [1,2]. This fact, in turn, has shifted the spectrum of HIV-related comorbidity and mortality away from opportunistic infections and toward chronic medical illnesses [1,2]. Understanding the biological basis of long-term complications related to HIV infection and treatment may unravel novel pathogenetic mechanisms, which might help the design of more focused and rational approaches for the diagnosis, prevention and treatment of HIV-related comorbidities. In this respect, the study by Teofili et al. represents a step ahead in understanding the biology of CAD in the HIV-positive population, and provides new concepts that may be applied to the search for novel diagnostic markers and prognosticators of HIV-related CAD.
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