Atherosclerosis in patients infected with HIV is influenced by a mutant monocyte chemoattractant protein-1 allele

Servei de Medicina Interna, Hospital Universitari de Sant Joan, 43201 Reus, Spain.
Circulation (Impact Factor: 14.43). 10/2004; 110(15):2204-9. DOI: 10.1161/01.CIR.0000143835.95029.7D
Source: PubMed


Patients infected with HIV present with premature atherosclerosis, and the 2 diseases share common pathogenic pathways. We investigated mutations in the monocyte chemoattractant protein-1 (MCP-1) and CCR-2 genes, which are known to control aspects of these pathways, to ascertain whether they are involved in atherogenesis in these patients.
We performed carotid and femoral artery ultrasonography to detect subclinical atherosclerosis in patients infected with HIV (n=183). MCP-1-2518G and CCR-2 64I polymorphisms were determined in the HIV group and in a population-based control group (n=348). We also determined MCP-1 circulating levels in the HIV group. The presence of MCP-1-2518G in the group of patients with subclinical atherosclerosis was significantly higher than in patients without atherosclerotic lesions (47.5% versus 18.2%, respectively; P<0.001). Furthermore, the patients with atherosclerotic lesions had higher MCP-1 plasma concentrations than did patients without lesions (74.15 [4.03] versus 57.81 [3.67] pg/mL, respectively; P=0.03). When adjusted for known cardiovascular risk factors, the MCP-1-2518G allele was associated with subclinical atherosclerosis (OR 5.72, 95% CI 1.74 to 18.80, P=0.004). Compared with measurements conducted approximately 2.5 years earlier in a subset of 40 patients, intima-media thickness (IMT) in the carotid artery progressed at a mean rate of 0.06 mm/y more rapidly in patients bearing the MCP-1-mutated allele (P=0.08).
HIV-infected patients with the MCP-1-2518G allele have a 5-fold increased risk for atherosclerosis, as assessed by ultrasonography.

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Available from: Jorge Joven, Sep 23, 2015
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    • "This is in contrast to TNF-alpha induced MCP-1 release, in which both ROS and NF-κB are required for transcriptional activation [54]. We have chosen to study MCP-1 production in endothelial cells as a readout for proinflammatory endothelial activation and dysfunction because it has been linked to cardiovascular diseases in a series of human and mouse studies [55], [56] as well as with HIV infection [36], [57]. "
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    ABSTRACT: With effective antiretroviral therapy (ART), cardiovascular diseases (CVD) are emerging as a major cause of morbidity and death in the aging HIV-infected population. To address whether HIV-Nef, a viral protein produced in infected cells even when virus production is halted by ART, can lead to endothelial activation and dysfunction, we tested Nef protein transfer to and activity in endothelial cells. We demonstrated that Nef is essential for major endothelial cell activating effects of HIV-infected Jurkat cells when in direct contact with the endothelium. In addition, we found that Nef protein in endothelial cells is sufficient to cause apoptosis, ROS generation and release of monocyte attractant protein-1 (MCP-1). The Nef protein-dependent endothelial activating effects can be best explained by our observation that Nef protein rapidly transfers from either HIV-infected or Nef-transfected Jurkat cells to endothelial cells between these two cell types. These results are of in vivo relevance as we demonstrated that Nef protein induces GFP transfer from T cells to endothelium in CD4.Nef.GFP transgenic mice and Nef is present in chimeric SIV-infected macaques. Analyzing the signal transduction effects of Nef in endothelial cells, we found that Nef-induced apoptosis is mediated through ROS-dependent mechanisms, while MCP-1 production is NF-kB dependent. Together, these data indicate that inhibition of Nef-associated pathways may be promising new therapeutic targets for reducing the risk for cardiovascular disease in the HIV-infected population.
    PLoS ONE 03/2014; 9(3):e91063. DOI:10.1371/journal.pone.0091063 · 3.23 Impact Factor
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    • "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). "
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    AIDS Research and Therapy 05/2013; 10(1):11. DOI:10.1186/1742-6405-10-11 · 1.46 Impact Factor
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    • "Improvement of quantification of plasma HIV-1 RNA levels during and after latent reservoir reactivation place a crucial role in HIV-1 eradication efforts. The overall result of past efforts has resulted in a life-long treatment that does not have the ability to eradicate HIV infection and bears toxicities and adverse effects that augur ill for health systems [3] [4]. ART improve quality and expectancy of life in patients with continued administration and access for Health systems. "
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