Treatment of hypertriglyceridemia and HIV: fenofibrate-induced changes in the expression of chemokine genes in circulating leukocytes
© Alonso-Villaverde et al; licensee BioMed Central Ltd. 2009
Received: 12 May 2009
Accepted: 23 November 2009
Published: 23 November 2009
Fenofibrate changed the expression of chemokine genes in circulating leukocytes of HIV-infected patients with hypertriglyceridemia. The data suggest that fenofibrate when effective in the treatment of lipoprotein abnormalities, may act as a modulator of systemic inflammation. This particular action, therefore, may also influence the clinical course of the disease.
The impact of mutant chemokine ligands and receptors in the host susceptibility to HIV infection, in the clinical course of the disease and in the development of new therapies has been extensively described . Chemokines have also been implicated in the higher rates of atherosclerosis observed in HIV-infected patients which has been partially attributed to either a direct effect of highly active antiretroviral therapies or the concomitant metabolic abnormalities [2–4]. Treatment of HIV infection, particularly with the use of protease inhibitors (PIs), can raise triglyceride levels to the threshold indicated for intervention. Therefore, the need to maintain viral suppression may be challenged by the need to treat abnormal lipid levels. Fibrates, ligands for peroxisome proliferator-activated receptor α (PPARα), represent an effective treatment for hypertriglyceridemia that reduce coronary events and delay progression of coronary atherosclerosis [5, 6]. We hypothesized that such a treatment with fenofibrate may change the expression of chemokine genes in tissues and that this effect could be readily observed in circulating leukocytes.
Results and Discussion
There were no significant differences among the three study groups for duration of HIV, age, body mass index and CD4+ T cell count. Although the challenge of adherence to drugs is substantial in routine HIV care, we found a good tolerance to fenofibrate, and no complaint was recorded. As expected, only in fenofibrate treated patients the decrease in fasting plasma triglyceride concentration was statistically significant as well as the increase in plasma HDL-cholesterol levels (Figure 1A). A reduction in plasma total cholesterol and MCP-1/CCL2 concentrations were also observed but it did not reach statistical significance.
With the rationale that the target for fenofibrate, PPARα, is expressed in leukocytes  we explored the mRNA expression of selected chemokine genes in whole blood. We found that with respect to untreated patients there was no change in the expression of chemokine receptors CX3CR1 and CXCR4 but the expression of CCR2 was significantly decreased in patients treated with fenofibrate (U-Mann-Whitney, p = 0.016; Figure 1B). Of note, CCR2 gene expression was positively correlated with CD4+ T cell count only in those patients that were undergoing fenofibrate treatment (Spearman, ρ = 0.7; p = 0.02). The expression of ligands for these receptors was clearly different. We did not find any significant effect of fenofibrate in the MCP-1/CCL2 gene expression. However, there was a significant decrease in the gene expression of the CX3CL1/Fractalkine in patients treated with fenofibrate with respect to untreated hypertriglyceridemic patients (U-Mann-Whitney, p = 0.038; Figure 1B). This is probably accompanied by decreased CX3CL1 plasma levels and a similar effect in the contiguous endothelial cells, which, in combination with the CCR2 decreased expression, could be beneficial with respect to the risk of atherosclerosis considering their well documented role in the local accumulation of monocytes [8, 9]. However, fenofibrate had an intriguing effect in SDF-1 expression neutralizing the significant decrease in its expression observed in untreated hypertriglyceridemics (U-Mann-Whitney, p = 0.026; Figure 1B), presumably increasing SDF-1 values. SDF-1 plays a significant role in HIV infection because it is the natural ligand for CXCR4 which is used by HIV T-tropic strains to enter into the cells in advanced stages of the disease . Additionally, although the interpretation of SDF-1 levels is difficult we have previously shown that the allelic variant SDF1-3'A appears to be protective against the development of carotid atherosclerosis .
In multivariate analysis, only fenofibrate treatment significantly contributed to explain CCR2 [B = 0.18 (0.003 to 0.09); P = 0.04] and SDF-1 [B = 4.6 (1.1 to 18.0); P = 0.03] expression levels in hypertriglyceridemic patients. This relationship, however, was not maintained in CX3CL1/Fractalkine expression [B = 0.23 (0.04 to 1.1); P = 0.07].
Therefore, our results show less lipid disturbances with the addition of fenofibrate in patients with HIV, which is accompanied by significant changes in the pattern of chemokine gene expression in circulating leukocytes. The data suggest that PPARα activators may be useful in the attempt to decrease the risk of atherosclerosis and may act as modulators of systemic inflammation and the associated vascular response. However, further studies in other type of populations without lipid abnormalities should be needed to confirm the fenofibrate effect or any lipid-lowering drug effect on systemic inflammation. Moreover, a note of caution should be added before the indication of these active drugs and further studies are needed to disregard potential deleterious effects on the HIV infection itself.
List of abbreviations
monocyte chemotactic protein-1
peroxisome proliferator-activated receptor α
stromal cell-derived factor-1.
GA, RB-D and AR are the recipients of a grant from Comissionat per a Universitats i Recerca del Departament d'Innovació, Universitats i Empresa de la Generalitat de Catalunya i del Fons Social Europeu.
- Reiche EM, Bonametti AM, Voltarelli JC, Morimoto HK, Watanabe MA: Genetic polymorphisms in the chemokine and chemokine receptors: impact on clinical course and therapy of the human immunodeficiency virus type 1 infection (HIV-1). Curr Med Chem. 2007, 14: 1325-1334. 10.2174/092986707780597934View ArticlePubMed
- Depairon M, Chessex S, Sudre P, Rodondi N, Doser N, Chave JP, Riesen W, Nicod P, Darioli R, Telenti A, Mooser V, Swiss HIV Cohort Study: Premature atherosclerosis in HIV-infected individualsfocus on protease inhibitor therapy. AIDS. 2001, 15: 329-334. 10.1097/00002030-200102160-00005View ArticlePubMed
- Alonso-Villaverde C, Coll B, Parra S, Montero M, Calvo N, Tous M, Joven J, Masana L: Atherosclerosis in patients infected with HIV is influenced by a mutant monocyte chemoattractant protein-1 allele. Circulation. 2004, 110: 2204-2209. 10.1161/01.CIR.0000143835.95029.7DView ArticlePubMed
- Hadigan C, Meigs JB, Corcoran C, Rietschel P, Piecuch S, Basgoz N, Davis B, Sax P, Stanley T, Wilson PW, D'Agostino RB, Grinspoon S: Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. Clin Infect Dis. 2001, 32: 130-139. 10.1086/317541View ArticlePubMed
- Rao A, D'Amico S, Balasubramanyam A, Maldonado M: Fenofibrate is effective in treating hypertriglyceridemia associated with HIV Lipodystrophy. Am J Med Sci. 2004, 327: 315-318. 10.1097/00000441-200406000-00003View ArticlePubMed
- Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V: Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987, 317: 1237-1245. 10.1056/NEJM198711123172001View ArticlePubMed
- Lee JW, Bajwa PJ, Carson MJ, Jeske DR, Cong Y, Elson CO, Lytle C, Straus DS: Fenofibrate represses interleukin-17 and interferon-gamma expression and improves colitis in interleukin-10-deficient mice. Gastroenterology. 2007, 133: 108-123. 10.1053/j.gastro.2007.03.113View ArticlePubMed
- Schulz C, Schäfer A, Stolla M, Kerstan S, Lorenz M, von Brühl ML, Schiemann M, Bauersachs J, Gloe T, Busch DH, Gawaz M, Massberg S: Chemokine fractalkine mediates leukocyte recruitment to inflammatory endothelial cells in flowing whole blood: a critical role for P-selectin expressed on activated platelets. Circulation. 2007, 116: 764-773. 10.1161/CIRCULATIONAHA.107.695189View ArticlePubMed
- Cheng C, Tempel D, van Haperen R, de Boer HC, Segers D, Huisman M, van Zonneveld AJ, Leenen PJ, Steen van der A, Serruys PW, de Crom R, Krams : Shear stress-induced changes in atherosclerotic plaque composition are modulated by chemokines. J Clin Invest. 2007, 117: 616-626. 10.1172/JCI28180PubMed CentralView ArticlePubMed
- Simmons G, Reeves JD, Hibbitts S, Stine JT, Gray PW, Proudfoot AE, Clapham PR: Co-receptor use by HIV and inhibition of HIV infection by chemokine receptor ligands. Immunol Rev. 2000, 177: 112-126. 10.1034/j.1600-065X.2000.17719.xView ArticlePubMed
- Coll B, Alonso-Villaverde C, Parra S, Montero M, Tous M, Joven J, Masana L: The stromal derived factor-1 mutated allele (SDF1-3'A) is associated with a lower incidence of atherosclerosis in HIV-infected patients. AIDS. 2005, 19: 1877-1883. 10.1097/01.aids.0000183516.22266.ddView ArticlePubMed
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