A possible role for CCR5 in the progression of atherosclerosis in HIV-infected patients: a cross-sectional study
© Fernández-Sender et al.; licensee BioMed Central Ltd. 2013
Received: 12 December 2012
Accepted: 7 May 2013
Published: 9 May 2013
Chemokines can block viral entry by interfering with HIV co-receptors and are recognised mediators of atherosclerosis development. A number of experimental drugs that inhibit HIV entry arrest the development of atherosclerosis in animal models. We hypothesised that the expression of chemokine receptors in circulating leukocytes is associated with the rate of atherosclerosis progression in HIV-infected patients.
The increase in intima-media thickness during a 2-year follow-up was used to classify HIV-infected patients (n = 178) as progressors (n = 142) or non-progressors (n = 36) with respect to atherosclerosis. Logistic regression was used to assess variables associated with atherosclerosis progression. Mutations in the CCR5Δ32, CCR2 64I, and CX3CR1 (T280M and V249I) co-receptors as well as the levels of CCR5, CXCR4, CX3CR1, and CCR2 mRNA expression in circulating leukocytes were analysed as independent variables.
Among the baseline variables, only genetic variants explained the dichotomous outcome. The expression of CCR2 and CXCR4 did not discriminate between progressors and non-progressors. Conversely, CCR5 and CX3CR1 expression was higher in not only progressors but also patients with detectable viral load. The logistic regression, however, demonstrated a significant role for CCR5 expression as a predictor of atherosclerosis progression (B = 2.1, OR = 8.1, p = 0.04) and a negligible effect for CXC3R1 and CCR2 expression.
Available CCR5 antagonists should be investigated for their potential to delay the course of atherosclerosis in HIV-infected patients.
KeywordsCardiovascular risk factors Chemokine receptors Genetic variants Inflammation Maraviroc
Current therapies achieve long-term remission and/or prevent morbid conditions associated with human immunodeficiency virus-1 (HIV-1) infection. Despite the ineffective elimination of the virus, correct management is accompanied by a growing increase in life expectancy that involves age-related complications. For example, atherosclerosis and other non-communicable diseases develop earlier and more rapidly in HIV patients compared with non-infected individuals of a similar age with similar risk factors [1–3].
Persistent immune activation may be the reason for this phenomenon, likely through host gene variations in chemokine responses to non-infectious particles or viral proteins [4–6]. Chemokines and chemokine receptors play a significant role in atherosclerosis, may influence susceptibility to HIV infection, and may affect the course of both diseases [6, 7]. The CC chemokines, which contain two adjacent cysteines near the amino terminus, are particularly important, and the role of CCL2, a ligand for CCR2, in the development of atherosclerosis has been substantiated in animal models and humans [5, 8]. Furthermore, orally bioavailable agents that inhibit the chemotaxis of primary CCR2-expressing human monocytes towards CCL2 are currently in various clinical trials [9, 10]. More recently, the chemokine receptor CCR5 and its ligands (CCL3, CCL4 and CCL5) have been implicated in the pathogenesis of atherosclerosis , and a relatively common mutation with a corresponding lack of function (CCR5 Δ32) confers relative resistance to HIV infection  and a reduction in susceptibility to coronary artery disease . These and other findings have facilitated the development and further approval of CCR5 antagonists (maraviroc) as antiretroviral agents in patients infected with strains that do not use CXCR4 as the co-receptor . It remains to be established whether maraviroc influences the development of atherosclerosis; however, we have recently identified the beneficial effects of both lipid metabolism and inflammation . Fractalkine (CX3CL1) and its receptor, CX3CR1, have also been implicated as modulators of both HIV infection and atherosclerosis, and functional polymorphisms in CXC3R1 (V249I and T280M) are clinically relevant during the course of these conditions [16, 17].
The available data are difficult to interpret because of the high redundancy of the chemokine system, conflicting results for the cardiovascular risk predictions, and effects from possible interactions among receptors, which could be confounding factors [16, 17]. In this study, we investigated for the first time whether the expression of chemokine receptors in circulating leukocytes was relevant for the assessment of atherosclerosis progression in HIV-infected patients. We determined that CCR5 expression in these cells might be a strong predictor of atherosclerosis progression, indicating a further therapeutic target for CCR5 antagonists.
Study design, population and standardised ultrasound protocol
This report was prepared in accordance with the STROBE guidelines described at http://www.strobe-statement.org/. The procedures were performed in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans, and the study was approved by the ethics committee at the Hospital Universitari de Sant Joan de Reus. Patients who accepted the invitation to participate in the study provided full informed consent. HIV-infected patients who attended our outpatient clinic were routinely asked to be incorporated into a cohort (n = 523) in accordance with previously described procedures [1, 6, 18]. None of the included patients were treated with CCR5 antagonists. In a retrospective, longitudinal study, we sampled a cross-section of the patients to assess the intima-media thickness (IMT) at baseline (when incorporated into the cohort) and 2 years later.
We used the LOGIQ 700 ME system (General Electric) to obtain normalised values IMT [1, 6]. We identified and digitally recorded the far wall of the common carotid artery (1 cm proximal to the bifurcation), the carotid bulb (in the bifurcation), and the internal carotid artery (1 cm distal from the bifurcation). The IMT measurements of each arterial segment were averaged and used in the statistical analyses as the combined IMT. We identified patients with a 2-year difference in the IMT value that was equal to or lower than the technical differences among examiners as non-progressors. This value was obtained via an intraclass correlation coefficient determined with 30 measurements (r = 0.89, p < 0.001) and established as 0.01 mm (standard deviation 0.02 mm). The progressors exhibited ΔIMT >0.01 mm and/or the presence of a previously unrecognised plaque in the second observation. The procedures were performed essentially as described previously [6, 19, 20]. To assess the reproducibility of the measurements, the images of 30 randomly selected patients were re-measured using the same protocol. The intraclass correlation coefficient between the 2 sets of measurements was 0.91, and the absolute difference in IMT was 0.007 mm (0.018). To assess the reproducibility of the rescanning and re-measurement, we also measured the inter-month correlation (r = 0.95; n = 15).
The other relevant data were collated from clinical records or obtained using standardised guidelines and routine laboratory methods [21, 22]. The covariates used were obtained in the same time frame for each participant. To avoid sampling bias, we selected and presented data only from patients who did not exhibit changes in variables or episodes that were likely to contribute to the outcome during follow-up (n = 217). The patients were observed by their attending doctors every 3 months, and no major events were recorded. Changes in the clinical and laboratory markers of cardiovascular risk and/or HIV infection were considered not relevant (less than 5% of differences with respect to the normal inter-day coefficient of variation for each measurement). The resulting study population was used to determine whether chemokine receptor expression in blood cells was associated with atherosclerosis progression, and additional fasting venous blood samples were drawn immediately before the second IMT measurement under conditions that guaranteed RNA preservation (using TEMPUS blood RNA tubes from Applied Biosystems, Foster City, CA). Inappropriately documented IMT measurements (n = 16), inappropriately handled samples (n = 9), and changes in the antiretroviral treatment (n = 14) were detected and considered exclusion criteria. Therefore, the data for 178 patients are presented. This number was considered sufficiently higher than the minimum sample size obtained (n = 121) according to available data [6, 19, 20] and assuming a difference between groups exceeding 10%, an overall standard deviation of 20%, and 80% power with a two-sided 5% significance level.
DNA genotyping and mRNA expression
Summary of taqman® gene expression assays used in this study*
Amplicon length (bp)
The data were presented as the means plus the standard error of the mean (in parentheses). The normality of the distributions was assessed using the Kolmogorov-Smirnov method. The groups were compared using Student’s unpaired t-test or Kruskal–Wallis one-way analysis. There were no adjustments for multiple testing for genetic analyses because the variants were not rare and the correspondence for their phenotypes was absent according to the described procedures . The χ2 test was used to compare categorical variables. Multivariate logistic regression stepwise analyses were performed to detect factors associated with the condition of progressors. Odds ratios were included when necessary. Allelic frequency descriptions and Hardy-Weinberg equilibrium tests were performed using freely available software (http://bioinfo.iconcologia.net/SNPstats). To create a “quasi-randomised” experiment, we used the propensity score analyses described previously [28–30]. For other measurements, we used SPSS software version 18.0 (SPSS Inc., Chicago, IL).
Results and discussion
In accordance with our expectations, most of the patients included in the study were considered progressors (n = 142); however, a substantial number of patients demonstrated no evidence of increased IMT values during the 2-year study (n = 36). The patients who demonstrated progression of subclinical atherosclerosis were treated with either an efavirenz-based regimen (38%) or protease inhibitors (39%), and a number of patients were left untreated. The majority of the patients maintained a low viral load. The treatment regimens for patients who did not demonstrate progression were similar. We did not observe a between-group difference in the lipid-lowering and/or hypoglycaemic treatments, and to avoid confusion, none of the patients were taking CCR5 antagonists.
Baseline participants’ clinical and laboratory characteristics blindly collated from medical records at the end of the study
Non-progressors (n = 36; 20%)
Progressors (n = 142; 80%)
Male, n (%)
Current smokers, n (%)
Systolic blood pressure, mm Hg
Diastolic blood pressure, mm Hg
Baseline IMT, mm
Final IMT, mm
Δ IMT, mm
Total cholesterol, mmol/L
HDL cholesterol, mmol/L
LDL cholesterol, mmol/L
Apolipoprotein A I, mmol/L
Lipodystrophy, n (%)
HVC co-infection, n (%)
HIV-1 RNA < 50 copies/mL, n (%)
CD4 cell count, cell/mm3
CD8 cell count, cell/mm3
Δ CD4 cell count, cell/mm3
Arguably, a 2-year follow-up might not be sufficient to evaluate the full effect of the variables. A longer follow-up to ascertain the role of host-related, genetically determined variants, however, is not feasible because the progression of carotid atherosclerosis in these patients is faster than in non-infected patients, and the evaluation of non-classical factors requires shorter periods [19, 20]. We have previously demonstrated non-concordance between subclinical atherosclerosis and the calculated Framingham risk score in HIV-infected patients . However, the issue of non-concordance is under debate and in a recent study, increased Framingham risk scores were associated with abnormal early and late surrogate markers of atherosclerosis. However, low scores were also associated with significant subclinical atherosclerosis in these patients .
Allelic frequency for selected polymorphisms as segregated according to the progression in IMT measurements during a two-year period
CXC3CR-1 249 V
CXC3CR-1 280 M
CCR2 62 I
Significant predictor variables found in multivariate logistic regression stepwise analysis used for the binary outcome (progressors and non-progressors) with respect to subclinical atherosclerosis
CI 95% for OR
CX3CR1 280 V
CX3CR1 249 M
Generally, we found that CCR5 expression is the best predictor of progression in atherosclerosis and that a number of host gene variants may have a significant effect. Although CCR2 and CX3CR1 are predisposing factors in atherosclerosis and inflammation [41, 42], we also determined that under these conditions, the effects of the expression of these receptors appeared negligible. This is not surprising because the expression of chemokines in different tissues can change in response to multiple stimuli .
The predominant role of CCR5 expression in circulating leukocytes in HIV-infected patients as a predictive factor for the rate of progression of atherosclerosis suggests that drugs affecting chemokines should be investigated for their role not only as protective agents in HIV-infection but also in atherosclerosis-related complications. This suggestion is in accordance with the observation that a number of experimental drugs that inhibit HIV entry can arrest the progression of atheroma plaques in animal models [45–47] and that CCR5 antagonists can affect cardiovascular risk factors [48, 49]. Therefore, we propose that available CCR5 antagonists that have been clinically validated should be considered as not only antiviral drugs but also potentially useful agents for the management of inflammation-related diseases.
Possible limitations of the study
Biases are particularly difficult to avoid in studies with these characteristics. However, in this study, recall bias and detection bias were essentially excluded from the design. We also excluded the possibility that the increase in the IMT measurement was sensitive to small, unmeasured confounders (hidden biases) because the patients were examined at least 8 times during the study according to a strict clinical protocol for the detection of the outcome and related variables. Additionally, covariate adjustment using propensity score analyses demonstrated good performance, with scores reflecting a low probability that the participant’s baseline characteristics played a role in the increase in IMT. Finally, we appreciate that the length of the follow-up may be important and should be considered carefully when replicating our findings.
The funding source and granting support played no role in the study design; in the collection, analysis and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. The Unitat de Recerca Biomèdica is financially supported by the Instituto de Salud Carlos III (Ministerio de Sanidad y Consumo y Fondo de Investigación Sanitaria) through competitive grants PI11/00130, PI11/02187, PI08/01381 and PI08/01175.
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