Effect of genetic variations in drug transporters, metabolizing enzyme and regulatory genes on the development of HIV-associated lipodystrophy.

Adipocytes play a crucial role in the metabolism of lipids and sugars. Their response varies depending on the circumstances or other factors influenced by physiological and metabolic stresses. People living with HIV (PLWH) experience different effects of HIV and highly active antiretroviral therapy (HAART) on their body fat. Some patients respond well to antiretroviral therapy (ART), while others taking similar regimens do not. The genetic makeup of patients has been strongly linked to the variable responses to HAART among PLWH. The cause of HIV-associated lipodystrophy syndrome (HALS) is not well understood, but it may be influenced by genetic variations in the host. The metabolism of lipid effectively modulates plasma triglyceride and high-density lipoprotein cholesterol levels in PLWH. Genes related to drug metabolism and transport play an important role in the transportation and metabolism of ART drugs. Genetic variation in metabolizing enzyme genes of antiretroviral drugs, lipid transport and transcription factor-related genes could interfere with fat storage and metabolism, contributing to the development of HALS. Hence we examined the impact of genes associated with transport, metabolism and various transcription factors in metabolic complications, and their impact on HALS. A study using databases such as PubMed, EMBASE and Google Scholar was conducted to understand the impact of these genes on metabolic complications and HALS. The present article discuss the changes in the expression and regulation of genes and their involvement in the lipid metabolism, lipolysis and lipogenesis pathways. Moreover, alteration of the drug transporter, metabolizing enzyme and various transcription factors can lead to HALS. Single-nucleotide polymorphisms in genes that play an essential role in drug metabolism and drug and lipid transportation may also contribute to individual differences in the emergence of metabolic and morphological alterations during HAART treatment.

Impact of inflammatory cytokine and adipokine gene variations in the development of HIV-associated lipodystrophy.

Cytokines affect lipid and glucose metabolism and also alter the body's habitus. They play a role in the development of lipodystrophy syndrome. Adipocytes secrete the pro-inflammatory cytokines IL-1, TNF-α and IL-6. The plasma cytokine concentration is associated with the percentage and distribution of fat tissue in the body. The metabolic disturbances are strongly associated with increased levels of pro-inflammatory cytokines (IL-1, IL-6 and TNF-α). Plasma levels of cytokines such as TNF-α, IL-6 and leptin were found to be increased while plasma resistin levels were found to be variable in patients suffering from obesity and type II diabetes mellitus. Until now, limited information has been available on the polymorphism of cytokine and adipokine genes in patients of HIV-associated lipodystrophy (HIVLD), which can contribute to individual variations in susceptibility to metabolic diseases, especially to HIVLD. Hence, we studied the association of cytokine and adipokine gene polymorphisms in various diseases and their impact on HIVLD. We carry out an extensive search using several databases, including PubMed, EMBASE and Google Scholar. The distribution of cytokine and adipokine gene polymorphisms and their expression levels varied among various populations. We examined the variants of cytokine and adipokine genes, which can contribute to individual variations in susceptibility to metabolic diseases, especially to HIVLD. In the current review, we present a brief account of the risk factors of HIVLD, the pathogenesis of HIVLD and the polymorphism of cytokine and adipokine genes in various diseases with special reference to their impact on HIVLD.

Genetic and cytometric analyses of subcutaneous adipose tissue in patients with hemophilia and HIV-associated lipodystrophy.

BACKGROUND: The authors recently performed plastic surgeries for a small number of patients with hemophilia, HIV infection, and morphologic evidence of lipodystrophy. Because the pathophysiological mechanism of HIV-associated lipodystrophy remains to be elucidated, we analyzed subcutaneous adipose tissues from the patients. METHODS: All six patients had previously been treated with older nucleoside analogue reverse-transcriptase inhibitors (NRTIs; stavudine, didanosine or zidovudine). Abdominal and inguinal subcutaneous fat samples were obtained from the HIV+ patients with hemophilia and HIV- healthy volunteers (n = 6 per group), and analyzed via DNA microarray, real-time PCR, flow cytometry and immunohistochemistry. RESULTS: The time from initial NRTI treatment to collecting samples were 21.7 years in average. Cytometric analysis revealed infiltration of inflammatory M1 macrophages into HIV-infected adipose tissue and depletion of adipose-derived stem cells, possibly due to exhaustion following sustained adipocyte death. Genetic analysis revealed that adipose tissue from HIV+ group had increased immune activation, mitochondrial toxicity, chronic inflammation, progressive fibrosis and adipocyte dysfunction (e.g. insulin resistance, inhibited adipocyte differentiation and accelerated apoptosis). Of note, both triglyceride synthesis and lipolysis were inhibited in adipose tissue from patients with HIV. CONCLUSIONS: Our findings provide important insights into the pathogenesis of HIV-associated lipodystrophy, suggesting that fat redistribution may critically depend on adipocytes' sensitivity to drug-induced mitochondrial toxicity, which may lead either to atrophy or metabolic complications.

Association of the polymorphisms of the genes APOC3 (rs2854116), ESR2 (rs3020450), HFE (rs1799945), MMP1 (rs1799750) and PPARG (rs1801282) with lipodystrophy in people living with HIV on antiretroviral therapy: a systematic review.

The aim of this study was to perform a systematic review to identify data reported in the literature concerning the association of APOC3 (rs2854116), ESR2 (rs3020450), HFE (rs1799945), MMP1 (rs1799750) and PPARG (rs1801282) polymorphisms with lipodystrophy in people living with HIV (PLWHIV) on antirretroviral therapy. The research was conducted in six databases and the studies were selected in two steps. First, a search was undertaken in the following electronic databases: PubMed, Science Direct, Medline, World Wide Science, Directory of Open Access Journals, Scielo, Lilacs and Medcarib. The titles and abstracts of 24,859 articles were read to select those that match the elegibilty criteria. Five papers that addressed the association of HAART, lipodystrophy and polymorphisms were selected for the review. There was no association between the polymorphisms of the genes APOC3 and PPARG and lipodystrophy. Another study described an association between the variant allele (G) of HFE and protection concerning the development of lipoatrophy (0.02) when compared with the reference allele (C). On the other hand, the variant allele (T) of the ESR2 gene was associated with the development of lipoatrophy (p = 0.007) when compared with the reference allele (C). In addition, the genotype and the variant allele of the gene MMP1 (2G) were associated with lipodystrophy in PLWHIV on HAART (p = 0.0002 and p = 0.0008, respectively). Therefore, further studies with other populations, involving PLWHIV on HAART are necessary to better understand the role of genetic markers, which may be involved in a predisposition to lipodystrophy.

Polymorphisms in adiponectin receptor genes are associated with lipodystrophy-related phenotypes in HIV-infected patients receiving antiretroviral therapy.

OBJECTIVES: Adiponectin is a circulating peptide secreted by mature adipocytes that may act as a regulator of glucose and lipid metabolism. This study aimed to investigate the association between genetic variability in the adiponectin receptor genes ADIPOR1 (adiponectin receptor 1) and ADIPOR2 and lipodystrophy and its related anthropometric and metabolic phenotypes in HIV-infected patients on highly active antiretroviral therapy (HAART). METHODS: We studied six single nucleotide polymorphisms (SNPs) in the adiponectin receptor genes ADIPOR1 (rs1342387 and rs10920533) and ADIPOR2 (rs11061925, rs10773983, rs929434 and rs767870) and their association with adiponectin plasma levels, lipodystrophy subtypes and other parameters linked to glucose and lipid metabolism involved in the lipodystrophic syndrome. The genotypes of 407 HIV-infected patients receiving HAART were investigated using real-time polymerase chain reaction. Mean biochemical and anthropometrical parameters were compared between the different genotypes using analysis of variance. RESULTS: Two ADIPOR2 SNPs (rs11061925 and rs929434) were associated with fasting plasma triglyceride concentrations in the entire sample. Stronger significant associations were found between these SNPs and biochemical parameters (levels of triglycerides, total cholesterol, adiponectin and glucose) in men. We did not find any significant associations with ADIPOR1 gene variants. CONCLUSIONS: SNPs in the ADIPOR2 gene appear to be involved in the metabolic alterations in HIV-infected men receiving HAART.

Immunohistochemical analysis of the expression of TNF-alpha, TGF-beta, and caspase-3 in subcutaneous tissue of patients with HIV lipodystrophy syndrome.

INTRODUCTION: HIV Lipodystrophy Syndrome (HIVLS) is a multifactorial clinical expression that presents alterations in the metabolism and distribution pattern of body fat via immunological changes capable of disrupting homeostasis. This study aimed to analyze the degree of inflammatory, anti-inflammatory, and apoptosis activity in the subcutaneous tissue of patients, based on the expression of Tumor Necrosis Factor-α (TNF-α), Transforming Growth Factor-ß (TGF-ß), and caspase-3, respectively, and correlate them with clinical data and with each other. METHODS: This is a cross-analytical study. The biopsy of subcutaneous cellular tissue was performed on the right thigh of 19 patients with HIVLS who were attended to at a university hospital, and four people without HIV and lipodystrophy, for comparison. The type of lipodystrophy and the estimation of body fat were obtained during the consultation or obtained from medical charts. The cytokine expression was observed in the adipose tissue through the streptavidin-biotin peroxidase method, and analyzed by optical microscopy. RESULTS: Despite the mixed clinical form having been prevalent in both genders, men were more lipoatrophic and women were more lipohypertrophic. Men showed higher expression of TNF-α and caspase-3 than women. Patients with lipodystrophy had higher expression of TNF-α and caspase-3 and lower TGF-ß, compared to the control group. The percentage of body fat was negatively correlated with the expression of TNF-α and caspase-3. Longer durations of infection and use of antiretroviral therapy (ARVT) were positively associated with the levels of TNF-α. The expression of caspase-3 and TGF-ß was associated with higher levels of TNF-α. CONCLUSION: Regardless of the clinical form, HIVLS is characterized by a chronic inflammatory process associated with the male gender, the percentage of body fat, and lipoatrophy manifestations. There is increased apoptotic activity in more inflamed tissues and there is correlation between TNF-α and TGF-ß, which suggests a possible negative feedback mechanism between the inflammatory and anti-inflammatory activity.

Identification of novel genetic variations in ABCB6 and GRN genes associated with HIV-associated lipodystrophy.

Protease inhibitors (PIs) are associated with an incidence of lipodystrophy among people living with HIV(PLHIV). Lipodystrophiesare characterised by the loss of adipose tissue. Evidence suggests that a patient's lipodystrophy phenotype is influenced by genetic mutation, age, gender, and environmental and genetic factors, such as single-nucleotide variants (SNVs). Pathogenic variants are considered to cause a more significant loss of adipose tissue compared to non-pathogenic. Lipid metabolising enzymes and transporter genes have a role in regulating lipoprotein metabolism and have been associated with lipodystrophy in HIV-infected patients (LDHIV). The long-term effect of the lipodystrophy syndrome is related to cardiovascular diseases (CVDs). Hence, we determined the SNVs of lipid metabolising enzymes and transporter genes in a total of 48 patient samples, of which 24 were with and 24 were without HIV-associated lipodystrophy (HIVLD) using next-generation sequencing. A panel of lipid metabolism, transport and elimination genes were sequenced. Three novel heterozygous non-synonymous variants at exon 8 (c.C1400A:p.S467Y, c.G1385A:p.G462E, and c.T1339C:p.S447P) in the ABCB6 gene were identified in patients with lipodystrophy. One homozygous non-synonymous SNV (exon5:c.T358C:p.S120P) in the GRN gene was identified in patients with lipodystrophy. One novelstop-gain SNV (exon5:c.C373T:p.Q125X) was found in the GRN gene among patients without lipodystrophy. Patients without lipodystrophy had one homozygous non-synonymous SNV (exon9:c.G1462T:p.G488C) in the ABCB6 gene. Our findings suggest that novel heterozygous non-synonymous variants in the ABCB6 gene may contribute to defective protein production, potentially intensifying the severity of lipodystrophy. Additionally, identifying a stop-gain SNV in the GRN gene among patients without lipodystrophy implies a potential role in the development of HIVLD.

RXRγ gene variants are associated with HIV lipodystrophy.

HIV lipodystrophy (HIVLD), associated with combination antiretroviral therapy (cART), leads to metabolic and cardiovascular diseases. Nuclear receptors play a central role in lipid homoeostasis and drug disposition; their genetic variants may predispose an individual to the development of HIVLD. DNA samples obtained from cART-treated HIV-positive patients with (HIVLD+; 124) and without (HIVLD-; 56) HIVLD were genotyped for 77 single nucleotide polymorphisms in nine nuclear receptor genes. Statistical analysis was carried out using Haploview software and by logistic regression. Three single nucleotide polymorphisms in RXRγ (rs2134095, rs113471, rs2194899) and its haplotypes (HIVLD+, 54%; HIVLD-, 40.6%; P=0.02) showed significant association with HIVLD. Multivariate analysis identified time since diagnosis (P=0.001) and carriage of the RXRγ haplotype (P=0.02) to be independently associated with HIVLD. Genetic variation in RXRγ, a common binding partner of nuclear receptors that modulate lipid homoeostasis and drug disposition, may contribute to the development of HIVLD in cART-treated HIV patients. These results need replication in other cohorts.

No longitudinal mitochondrial DNA sequence changes in HIV-infected individuals with and without lipoatrophy.

The potential for mitochondrial (mt) DNA mutation accumulation during antiretroviral therapy (ART), and preferential accumulation in patients with lipoatrophy compared with control participants, remains controversial. We sequenced the entire mitochondrial genome, both before ART and after ART exposure, in 29 human immunodeficiency virus (HIV)-infected Swiss HIV Cohort Study participants initiating a first-line thymidine analogue-containing ART regimen. No accumulation of mtDNA mutations or deletions was detected in 13 participants who developed lipoatrophy or in 16 control participants after significant and comparable ART exposure (median duration, 3.3 and 3.7 years, respectively). In HIV-infected persons, the development of lipoatrophy is unlikely to be associated with accumulation of mtDNA mutations detectable in peripheral blood.

Adipogenic gene variants in patients with HIV-associated lipodystrophy.

OBJECTIVES: Although highly active antiretroviral therapy (HAART) has been hugely beneficial in the treatment of HIV, HIV lipodystrophy (HIVLD) associated with HAART is a serious adverse effect, with long-term consequences including metabolic disturbances and an increased risk of atherosclerotic disease. Although HIVLD is clearly related to the drug regimen, individual susceptibility also plays a role. We hypothesized that variation in genes regulating adipogenesis, and in those implicated in inherited forms of lipodystrophy, may predispose to the development of HIVLD. METHODS: DNA samples were obtained from 180 HAART-treatedHIV+ patients: 124 with HIVLD (HIVLD+) and 56 without HIVLD (HIVLD-). Diagnosis of HIVLD was carried out by clinician's confirmation of patient self-report. High-throughput genotyping using Sequenom was used to screen 62 single nucleotide polymorphisms (SNPs) in eight genes involved in adipogenesis and inherited forms of lipodystrophy. Statistical analysis was performed using Haploview. Multivariate analysis (logistic regression) was used to identify independent predictors of HIVLD development in HAART-treated patients. RESULTS: SNPs in two adipogenesis regulators, LPIN1 and CEBPα, showed a significant association with HIVLD whereas a SNP in ZMPSTE24, a zinc metalloproteinase involved in prelamin A processing, showed a trend toward significance. Multivariate analysis identified time since HIV diagnosis (P=0.001) and carriage of more than one associated allele (P=0.008) to be the most significant independent predictors for the development of HIVLD. CONCLUSION: Genetic variation in key regulators of adipogenesis could interfere with fat storage and metabolism contributing to the development of HIVLD in HAART-treated HIV patients. These results need replication in other cohorts.

A study of fatty acid binding protein 4 in HIV-1 infection and in combination antiretroviral therapy-related metabolic disturbances and lipodystrophy.

OBJECTIVE: The aim of the study was to determine circulating levels of fatty acid binding protein 4 (FABP-4) in a cohort of HIV-1-infected patients treated with combination antiretroviral therapy (cART) and to investigate the relationships between FABP-4 levels and insulin resistance, dyslipidaemia, lipodystrophy and levels of proinflammatory adipocytokines in these patients. METHODS: A total of 282 HIV-1-infected patients treated with stable cART for at least 1 year (132 with lipodystrophy and 150 without) and 185 uninfected controls (UCs) were included in the study. Anthropometric parameters were determined. Plasma levels of FABP-4, soluble tumour necrosis factor receptors 1 and 2 (sTNF-R1 and sTNF-R2), interleukin-18 (IL-18), IL-6, adiponectin and leptin were also analysed. Insulin resistance was determined using the homeostasis model assessment of insulin resistance (HOMA-IR). Subcutaneous adipose tissue mRNA expression of proinflammatory cytokines was assessed in 38 patients (25 with lipodystrophy and 13 without) by real-time polymerase chain reaction (PCR). RESULTS: The plasma FABP-4 concentration was significantly higher in patients with lipodystrophy than in those without (P=0.012). FABP-4 concentration was positively correlated with body mass index (BMI), HOMA-IR, and the concentrations of insulin, total cholesterol, triglycerides, sTNF-R1, leptin and IL-18, but showed a negative correlation with high-density lipoprotein (HDL) cholesterol and adiponectin concentrations. After adjusting for age, sex and BMI, the odds ratio (OR) for risk of lipodystrophy was found to be significantly increased for those with the highest levels of FABP-4 [OR 0.838, 95% confidence interval (CI) 0.435-1.616 for medium FABP-4 vs. OR 2.281, 95% CI 1.163-4.475 for high FABP-4]. In a stepwise regression model, FABP-4 was independently associated with HOMA-IR after controlling for clinical and inflammatory parameters (P=0.004). Moreover, a positive relationship was observed in patients with lipodystrophy between subcutaneous adipose tissue CD68 expression and FABP-4 plasma levels (r=0.525; P=0.031). CONCLUSIONS: cART-treated HIV-1-infected patients with lipodystrophy have a systemic overproduction of FABP-4, which is closely linked to insulin resistance and inflammatory markers in subcutaneous adipose tissue.

[Association between the change regularity of peripheral blood mononuclear cell mitochondrial deoxyribonucleic acid content and human immunodeficiency virus-related lipodystrophy].

OBJECTIVE: To investigate the change regularity of peripheral blood mononuclear cell (PBMC) mtDNA (mitochondrial deoxyribonucleic acid) content and its association with HIV-LD (human immunodeficiency virus-related lipodystrophy) in HAART (highly active antiretroviral therapy). METHODS: At baseline, Months 6 and 24 of therapy, the cryopreserved PBMC were collected from 33 patients on a regular follow-up at our clinic. Among them, 17 had HIV-LD. Then total DNA was extracted and mtDNA content quantified by real-time PCR (polymerase chain reaction). RESULTS: The HIV/AIDS patients had a lower content of PBMC mtDNA (2(-ΔΔCt)) than the healthy controls at baseline (9.578 vs 17.195, P < 0.01). The mtDNA content was lower in the HIV-LD group than that in the no LD (NLD) group at each time point of therapy (13.619 vs 5.775, 6.360 vs 1.387, 7.170 vs 1.266, all P < 0.05). In the HIV-LD group, the half- and 2-year PBMC mtDNA content was markedly lower than those at baseline (both P < 0.05). And the change of mtDNA content (within half a year) was earlier than the onset of clinical HIV-LD at one year later. In the NLD group, the PBMC mtDNA content have an insignificant change after therapy. The mtDNA content decreased significantly in stavudine (d4T)-containing regimen group after treatment (P < 0.01), but showed no significant change in zidovudine (AZT)-containing regimen group after therapy. CONCLUSION: The decreased content of PBMC mtDNA after HIV infection and during HAART therapy is associated with HIV-LD. Nucleoside reverse transcriptase inhibitor, especially d4T, plays an important role in the progression of HIV-LD.

Interleukin-18 and interferon-gamma polymorphisms in Brazilian human immunodeficiency virus-1-infected patients presenting with lipodystrophy syndrome.

Cytokines play important roles in the pathogenesis of lipodystrophy syndrome (LS). Single nucleotide polymorphisms (SNPs) at positions -607(C/A) and -137(C/G) in the promoter region of the interleukin-18 (IL-18) gene and at position +874(T/A) of the interferon-gamma (IFN-gamma) gene are related to the expression of these cytokines. To examine whether IL-18 and IFN-gamma polymorphisms are associated with LS, these SNPs were genotyped in 88 human immunodeficiency virus (HIV)-infected patients presenting LS, 79 HIV-infected without LS, and 133 healthy controls. The -607A allele, -607AA genotype, and -137G/-607A and -137C/-607A haplotypes in the IL-18 gene were over-represented in HIV patients presenting LS. The -137G/-607C haplotype was associated with protection against LS. These results indicate that the -607(C/A) SNP is associated with LS development in HIV-infected patients.

TNF microsatellite alleles may confer protection against the development of lipodystrophy syndrome in Brazilian HIV patients.

The aim of this study was to evaluate the frequency of TNFa-e microsatellites and the promoter region (TNF-308 and TNF-238) in HIV/AIDS-infected patients presenting or not lipodystrophy syndrome (LS). The design is the genetic case-control association study. Microsatellite and the TNF promoter region polymorphisms were amplified by PCR and submitted to polyacrylamide gel electrophoresis. The genotypes and allele frequencies for 67 HIV-positive patients with lipodystrophy were compared with 50 HIV-positive patients with no evidence of lipodystrophy and with 131 healthy HIV-negative individuals. The presence of the TNFa5 allele could provide HIV/AIDS patients with protection against developing LS. The presence of TNF-308G allele, as well as of its homozygote TNF-308GG, were associated with susceptibility to developing LS. In addition, the presence of the haplotype TNFe3-d3-238G-308A-c1-a5-b7 suggests protection against developing that syndrome. This study highlights that polymorphic sites spanning the region nearby the TNF locus are associated with LS development in HIV/AIDS patients.

Subjective clinical lipoatrophy assessment correlates with DEXA-measured limb fat.

OBJECTIVES: Although physician- and patient-rated diagnoses of lipoatrophy are currently used as a basis for inclusion into clinical trials, few studies have compared physician- or patient-rated lipoatrophy severity with objective measures. We aim to assess the validity of physician- and patient-rated diagnoses of lipoatrophy by evaluating the correlation between clinical assessments of lipoatrophy and objective fat indices. METHODS: This cross-sectional study evaluated the association between clinical lipoatrophy scores and DEXA-measured limb fat (n = 154) and subcutaneous fat mitochondrial DNA (mtDNA) levels (n = 80) in HIV+ individuals. RESULTS: There was a significant negative correlation between DEXA-measured limb fat and lipoatrophy scores generated by either the patients (r = -0.27, p = .008) or the physician (r = -0.48, p < .0001). Also, a significant positive correlation was found between the patient-generated lipoatrophy score and the physician score (r = 0.68, p < .0001). However, there was no correlation between fat mtDNA levels and DEXA-measured limb fat (r = -0.09, p = .42) or between physician- or patient-generated lipoatrophy scores (r = -0.09, p = .43, and r = 0.04, p = .71, respectively). CONCLUSION: These results suggest that physician- and patient-rated lipoatrophy scores may be useful surrogates for more expensive measures of lipoatrophy, which could be reserved for research studies.

Mitochondrial DNA haplogroups and highly active antiretroviral therapy-related lipodystrophy.

BACKGROUND: The combination of different point mutations in mitochondrial DNA (mtDNA), which are defined as haplogroups, may cause modification in organelle function and may be involved in several pathologies. We analyzed the distribution of mtDNA polymorphisms in human immunodeficiency virus (HIV)-infected patients with lipodystrophy, a relevant adverse event caused by highly active antiretroviral therapy, and their correlation with metabolic and viroimmunologic parameters. METHODS: The frequency of the 9 most common European haplogroups was investigated in 346 white, HIV-infected patients with lipodystrophy. Haplogroups were identified on the basis of classic methods. Statistical analysis was performed with use of 1-way analysis of variance, the chi(2) test, and principal-components analysis. RESULTS: The distribution of mtDNA haplogroups among patients with lipodystrophy was similar to that among the general European population. We found no differences between patients with different haplogroups with regard to viroimmunologic results (plasma HIV load, CD4(+) T cell count, and nadir CD4(+) T cell count), glucose data (glucose, insulin, C-peptide, and glycosylated hemoglobin concentrations and insulin resistance), lipid data (levels of triglycerides, total cholesterol, high- and low-density lipoproteins, and apolipoprotein A1 and B), acid-base balance parameters (lactate level and anion gap), or anthropometric measures (weight, body mass index, and waist-to-hip ratio). No differences were observed in trunk fat levels, leg-fat ratio (which was determined by dual-energy x-ray absorptiometry), or exposure to different drug classes. Principal-components analysis confirmed that the spatial distribution of patients belonging to a given haplogroup was not influenced by different clinical parameters. CONCLUSIONS: Our study indicates that, in HIV-infected patients with lipodystrophy, mtDNA haplogroups are not related to major metabolic changes or to particular viroimmunologic features.

Association of APOC3 polymorphisms with both dyslipidemia and lipoatrophy in HAART-receiving patients.

The incidence and the magnitude of lipodystrophy and dyslipidemia in HIV-treated people reported in previous studies are very variable. Several predisposing factors have been identified, but there are few data on genetic factors. To search for a correlation between APOC3 polymorphisms and lipid disorders and lipodystrophy in HIV patients under d4T and protease inhibitors (PI)-containing HAART, we designed a monocenter, cross-sectional study in a University Hospital in Southern France during the period 2001-2004. Forty patients under HAART were included, with d4T for > or = 2 years and PI for > or = 1 year. We determined body mass composition by DXA, lipoprotein markers, and the -455/-482 apo C3 genotypes. Carriers of APOC3 variant alleles (-455 1/-482 1) displayed higher levels of triglycerides (3.72 vs. 2.57 mmol/liter), apo C3 (45.3 vs. 34.5 mg/liter), and apo E (130.2 vs. 66.5 mg/liter) and a lower fat mass (13.9 vs. 19.7%) than patients with nonvariant alleles (-455 0/-482 0). APOC3 polymorphisms might be associated with both dyslipidemia and lipoatrophy in HAART-treated patients.

Toxicogenetics of antiretroviral therapy: genetic factors that contribute to metabolic complications.

Metabolic complications of antiretroviral therapy (ART) have emerged as a major concern for long-term, successful management of HIV infection. Variability in the response to ART between individuals has been increasingly linked to the genetic background of patients, as regards efficacy and susceptibility to adverse reactions (toxicogenetics). This review summarizes the biological and methodological background for the genetic prediction of metabolic toxicity of ART. Recent studies are discussed which suggest that single-nucleotide polymorphisms (SNPs) in several genes involved in lipid metabolism and lipid transport in the general population (ABCA1, APOA5, APOC3, APOE, CETP) might modulate plasma triglyceride and high-density lipoprotein cholesterol levels in HIV-infected patients. At present, genetic prediction of lipodystrophy is not possible. Lipodystrophy has been linked to an accumulation of mtDNA mutations, a finding causally associated with ageing phenotypes in animal models. No mutations in LMNA, a gene linked to rare, inherited forms of lipodystrophy, have been identified in small studies of patients with lipodystrophy, and a possible link to a TNF promoter SNP remains to be confirmed. With the rapidly decreasing cost of genetic testing, the main issues that need to be addressed prior to introduction of toxicogenetic prediction in HIV clinical practice include reproducibly high predictive values of SNP associations with clinically relevant and well defined metabolic outcomes, studies that evaluate the contribution of SNPs in the context of multi-SNP and haplotype analysis, and the validation of genetic markers in independent, large patient cohorts. Comprehensive, whole genome approaches are increasingly being used.

Altered expression of nucleoside transporter genes (SLC28 and SLC29) in adipose tissue from HIV-1-infected patients.

BACKGROUND: Nucleoside transporter proteins (NTs) encoded by members of the SLC28 and SLC29 gene families contribute to nucleoside and nucleobase recycling but also modulate extracellular adenosine levels and thus adenosine-regulated metabolic targets. METHODS: We have examined the expression pattern of NT-encoding genes in human adipose tissue and we have further analysed whether the mRNA related to these genes show changes in their amounts associated with either HIV-1 infection, highly active antiretroviral therapy (HAART) or development of HIV-1-associated lipodystrophy syndrome (HALS). RESULTS: Human adipocytes express SLC28A1, SLC28A2 and SLC28A3 (encoding hCNT1, hCNT2 and hCNT3, respectively) and SLC29A1 and SLC29A2 (encoding hENT1 and hENT2, respectively). HIV-1 infection, prior to HAART and HALS development, is associated with the upregulation of the mRNA levels of the genes encoding hCNT1, hCNT3 and hENT2. The increase in the mRNA amounts for the former two genes may be due to the action of tumour necrosis factor-alpha (TNF-alpha), a cytokine with enhanced expression in adipose tissue following HIV-1 infection, as the effect is also observed in human adipocytes in culture after treatment with TNF-alpha. HAART and HALS development are associated with the upregulation of the mRNA levels encoding hCNT2 and hENT1, and further enhancement of hCNT1, hCNT3 and hENT2 gene expression. CONCLUSIONS: These data suggest that selected genes of the SLC28 and SLC29 families are not only targets of HIV-1 infection, but might also contribute to the development of adipose tissue alterations leading to lipodystrophy.

Dysfunctional Subcutaneous Fat With Reduced Dicer and Brown Adipose Tissue Gene Expression in HIV-Infected Patients.

CONTEXT: HIV patients are at an increased risk for cardiometabolic disease secondary to depot-specific alterations in adipose function, but mechanisms remain poorly understood. OBJECTIVE: The endoribonuclease Dicer has been linked to the modulation of brown and white adipocyte differentiation. We previously demonstrated that Dicer knockout mice undergo transformation of brown adipose tissue to white adipose tissue and develop a lipodystrophic phenotype. We hypothesized reduced Dicer and brown adipose tissue gene expression from nonlipomatous sc fat among HIV patients with a lipodystrophic phenotype. DESIGN: Eighteen HIV (nine with and without lipodystrophic changes in fat distribution, characterized by excess dorsocervical adipose tissue [DCAT]) and nine non-HIV subjects underwent punch biopsy of abdominal sc fat to determine expression of Dicer and other adipose-related genes. RESULTS: HIV subjects with long-duration antiretroviral use demonstrated excess DCAT vs non-HIV subjects (9.8 ± 1.0 vs 6.6 ± 0.8 cm(2), P = .02) with similar body mass index. Dicer expression was decreased in abdominal sc fat of HIV vs non-HIV (4.88 [1.91, 11.93] vs 17.69 [10.72, 47.91], P = .01), as were PPARα, ZIC1, PRDM16, DIO2, and HSP60 (all P ≤ .03). Moreover, the expression of Dicer (2.49 [0.02, 4.88] vs 11.20 [4.83, 21.45], P = .006), brown fat (PPARα [P = .002], ZIC1 [P = .004], LHX8 [P = .03], PRDM16 [P = .0008], PAT2 [P = .008], P2RX5 [P = .02]), beige fat (TMEM26 [P = .004], CD137 [P = .008]), and other genes (DIO2 [P = .002], leptin [P = .003], HSP60 [P = .0004]) was further decreased in abdominal sc fat comparing HIV subjects with vs without excess DCAT. Down-regulation of Dicer in the abdominal sc fat correlated with the down-regulation of all brown and beige fat genes (all P ≤ .01). CONCLUSION: Our results demonstrate dysfunctional sc adipose tissue marked by reduced Dicer in relationship to the down-regulation of brown and beige fat-related genes in lipodystrophic HIV patients and may provide a novel mechanism for metabolic dysregulation. A strategy to increase browning of white adipose tissue may improve cardiometabolic health in HIV.