Sandra Parra

Atherosclerosis in Patients Infected With HIV Is Influenced by a Mutant Monocyte Chemoattractant Protein-1 Allele

Background—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. Methods and Results—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 ≈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). Conclusions—HIV-infected patients with the MCP-1–2518G allele have a 5-fold increased risk for atherosclerosis, as assessed by ultrasonography.

Nonconcordance between subclinical atherosclerosis and the calculated Framingham risk score in HIV-infected patients: relationships with serum markers of oxidation and inflammation.

HIV‐infected patients show an increased cardiovascular disease (CVD) risk resulting, essentially, from metabolic disturbances related to chronic infection and antiretroviral treatments. The aims of this study were: (1) to evaluate the agreement between the CVD risk estimated using the Framingham risk score (FRS) and the observed presence of subclinical atherosclerosis in HIV‐infected patients; (2) to investigate the relationships between CVD and plasma biomarkers of oxidation and inflammation.

The Role of Immunity and Inflammation in the Progression of Atherosclerosis in Patients With HIV Infection

Background and Purpose— The initial steps of atherosclerosis and the entry of HIV into the cell share similar biological mechanisms. Therefore, our hypothesis is that the progression of atherosclerosis in patients with HIV infection can be influenced by variations in genes implicated in both processes. Methods and Results— The progression of atherosclerosis over a 2-year follow-up period was measured as the combined carotid and femoral intima media thickness (IMT) in 141 patients with HIV infection. The &Dgr;IMT (IMTfollow-up−IMTbaseline) values were used to segregate patients as minimal progressors or regressors (lowest &Dgr;IMT tertile), slow progressors (mid &Dgr;IMT tertile), and rapid progressors (highest &Dgr;IMT tertile). Mutations CCR-5&Dgr;32, CCR-2 64I, MCP-1-2518G, SDF1-3′A, and CX3CR-1 (T280 mol/L and V249I) in the host DNA were determined. Mean age of the patients was 38.96 (SEM: 0.61) and 68.8% were male. The mean &Dgr;IMT was 0.045 mm (0.01) per year, which represented a significant progression (P<0.001) with respect to baseline values. Patients with minimal progression or regression had a significantly (P=0.01) higher CD4 cell count than slow progressors and rapid progressors. Multivariate analyses indicated that age and total cholesterol were positively associated with IMT progression. In contrast, the CD4 cell count, the SDF1-3′A, and the CX3CR-1 249 I mutated alleles were associated with lesser IMT progression. Conclusion— The course of atherosclerosis in patients with HIV infection is influenced by polymorphisms in the SDF1 and CX3CR1 genes by metabolic variables and by the CD4 cell count. These data would be of help in assessing therapeutic needs of these patients.

Ezetimibe effectively decreases LDL-cholesterol in HIV-infected patients.

We tested the security and efficacy of ezetimibe in the treatment of HIV-associated dyslipemia. Twenty HIV-infected patients were randomly assigned to receive ezetimibe 10 mg/day or fluvastatin 80 mg/day. Patients receiving ezetimibe experienced a statistically significant (P = 0.003) 20% reduction in the concentration of LDL-cholesterol, similar to that observed with fluvastatin (24%, P between groups 0.70). We concluded that ezetimibe monotherapy effectively decreases LDL-cholesterol in HIV-infected patients.

The stromal derived factor-1 mutated allele (SDF1-3'A) is associated with a lower incidence of atherosclerosis in HIV-infected patients.

Background:HIV-infected patients have higher rates of subclinical atherosclerosis. The chemokine stromal derived factor 1 (SDF-1) is the natural ligand for the CXCR4 HIV co-receptor, is highly expressed in atherosclerotic plaques, and the plasma concentration is lower in individuals homozygous for the mutant allele (SDF1-3′A). We tested the influence of SDF1-3′A on atherosclerosis in HIV-infected patients. Methods:We performed carotid ultrasonography and determined the SDF1-3′A DNA polymorphism in 183 HIV-infected patients. Classical cardiovascular risk factors and antiretroviral therapy were also recorded. From these patients, we selected a group of 134 patients taking protease inhibitor-based antiretroviral therapy and in whom the lipid profile over an 18-month follow-up was collated. Results:We found atherosclerosis in 113 (61.7%) and a lower number of patients with the SDF-1 mutated allele in the group with carotid atherosclerosis compared to those without (41.6% versus 57.1%; P = 0.04). Using a logistic regression analysis, age and dyslipidaemia were significantly associated with atherosclerosis but the SDF1-3′A allele exerted a protective effect on the development of atherosclerosis (odds ratio, 0.45; 95% confidence interval, 0.14–1.02; P = 0.05). Further, we observed that, in the selected group of patients there were lower plasma low-density lipoprotein cholesterol concentrations [mean ± SEM, 2.06 ± 0.34 mmol/l] throughout follow up in those patients without carotid lesions and who also carried the mutated SDF1-3′A allele (P = 0.04). Conclusion:The SDF1-3′A allele is associated with a lower presence of subclinical carotid atherosclerosis in an HIV-infected population.

Paraoxonase-1 Gene Haplotypes Are Associated with Metabolic Disturbances, Atherosclerosis, and Immunologic Outcome in HIV-Infected Patients

BACKGROUND Oxidative stress is associated with human immunodeficiency virus (HIV) infection. Paraoxonase-1 (PON1) is an antioxidant enzyme that is bound to high-density lipoproteins (HDLs). We evaluated whether PON1 gene haplotypes influence the metabolic disturbances, presence of subclinical atherosclerosis, and virologic outcome associated with the infection. METHODS DNA from blood samples collected from 234 HIV-infected patients and 633 healthy control subjects had single-nucleotide polymorphisms of PON1(192), PON1(55), PON1(-162), PON1(-832), PON1(-909), PON1(-1076), and PON1(-1741) analyzed using the Iplex Gold MassArray method. Subsequently, the influence of these single-nucleotide polymorphisms on measured biochemical and clinical variables was assessed. RESULTS We observed significant differences in the haplotype distribution between the control subjects and the HIV-infected patients. Haplotype H10 (GTCCGTC) was more prevalent in the HIV-infected patients (6.41% vs 0.64%; P < .001), and haplotype H5 (GACCGTC) was less prevalent in HIV-infected patients (27.7% vs 42.9%; P = .001). In HIV-infected patients, haplotype H7 (AATTCCT) was associated with better CD4(+) cell count recovery, higher levels of HDL cholesterol (P = .048) and apolipoprotein A-I (P = .019), lower levels of triglycerides (P = .004), and lower rates of subclinical arteriosclerosis (P < .001). CONCLUSIONS PON1 haplotypes segregate with HIV infection, HDL metabolism, the presence of subclinical atherosclerosis, and CD4(+) cell recovery after treatment.

Circulating FABP4 is a marker of metabolic and cardiovascular risk in SLE patients.

The aim of this study is to determine if circulating fatty acid-binding protein 4 (FABP4) plasma levels are a possible marker of metabolic risk in SLE patients. Circulating levels of adipose FABP4 are associated with adiposity, insulin resistance (IR), metabolic syndrome, diabetes and cardiovascular diseases. Patients affected by systemic lupus erythematosus (SLE) show an accelerated atherosclerosis that cannot be entirely explained by traditional cardiovascular risk factors. Sixty consecutive patients with SLE and 34 non-SLE age-matched controls were recruited for the study. Total plasma lipids and circulating FABP4 were determined. Subclinical atherosclerosis was evaluated by measuring carotid intimae-media thickness (c-IMT) by sonography, and the distribution of lipoprotein subclasses was analysed by nuclear magnetic resonance (NMR) spectroscopy. In the SLE group, FABP4 was associated with IR, atherogenic dyslipidaemia, as measured by NMR, and the presence of subclinical atherosclerosis. In multivariate analyses FABP4 was associated with increased c-IMT independent of the inflammatory state of the patient. In sum, circulating FABP4 is involved in the metabolic disturbances of SLE affecting lipid metabolism and IR, and it could be a biomarker of atherosclerosis in this population.

Methodological constraints in interpreting serum paraoxonase-1 activity measurements: an example from a study in HIV-infected patients

BackgroundParaoxonase-1 (PON1) is an antioxidant enzyme that attenuates the production of the monocyte chemoattractant protein-1 (MCP-1) in vitro. Although oxidation and inflammation are closely related processes, the association between PON1 and MCP-1 has not been completely characterised due, probably, to that the current use of synthetic substrates for PON1 measurement limits the interpretation of the data. In the present study, we explored the relationships between the circulating levels of PON1 and MCP-1 in human immunodeficiency virus-infected patients in relation to the multifunctional capabilities of PON1.MethodsWe measured selected variables in 227 patients and in a control group of 409 participants. Serum PON1 esterase and lactonase activities were measured as the rates of hydrolysis of paraoxon and of 5-(thiobutyl)-butyrolactone, respectively. Oxidised LDL and MCP-1 concentrations were determined by enzyme-linked immunosorbent assay. High-density lipoproteins cholesterol, apolipoprotein A-I, and C-reactive protein concentrations were measured by standard automated methods.ResultsThere were significant relationships between PON1 activity and several indices of oxidation and inflammation in control subjects and in infected patients. However, these relationships varied not only with disease status but also on the type of substrate used for PON1 measurement.ConclusionThe present study is a cautionary tale highlighting that results of clinical studies on PON1 may vary depending on the methods used as well as the disease studied. Until more specific methods using physiologically-akin substrates are developed for PON1 measurement, we suggest the simultaneous employment of at least two different substrates in order to improve the reliability of the results obtained.

Influence of a monocyte chemoattractant protein 1 mutated allele on the response to protease inhibitor-based antiretroviral therapy

Antiretroviral drug efficacy has been widely studied in relation to viral factors. Mutations in the HIV co‐receptors and their natural chemokines, however, may be critical in HIV infection and treatment response. We compared the efficacy of protease inhibitor (PI) treatment among PI‐naïve patients grouped according to whether they carried the chemokine CC motif receptor 2 (CCR‐2) 64I and monocyte chemoattractant protein 1 (MCP‐1)–2518G alleles.

The pleiotropic role of HDL in autoimmune diseases.

As is widely known, the classic function of HDL is reverse cholesterol transport (RCT), thus removing cholesterol from peripheral tissues. Early epidemiological studies, such as Framinghams, stated that increased HDL levels were associated with a significant decrease in relative risk for cardiovascular disease (CVD) mortality. However, those with heightened expectations in recent years for the development of therapeutic targets to increase HDL levels have been disappointed, because efforts have demonstrated the opposite effect on cardiovascular and global mortality. However, in contrast, studies have highlighted the complexity and the intriguing role of HDL in different pathological conditions, such as infections, neoplasms, and autoimmune diseases. In this review an attempt is made to summarize some biological pathways that link HDL function with the immune system, and its possible clinical repercussions in autoimmune diseases.