The lipodystrophic syndrome is a frequent medical condition found in HIV-infected patients, characterized by redistribution of the body fat (lipoatrophy and fat accumulation) and metabolical abnormalities (hyperlipidemia, insulin resistance, hyperlactatemia). Different series have reported a variable prevalence of the lipodystrophic syndrome in HIV-infected patients on HAART, between 17 and 75%, probably due to clinical variability in diagnosis of lipodystrophic syndrome [1–7]. Early reports have associated the lipodystrophic syndrome with the use of different protease inhibitors [1,2]. Later reports have linked lipodystrophic syndrome to the use of thymidine nucleoside analogues that produce mitochondrial toxicity, hyperlactatemia and lipoatrophy [8–11]. The lipodystrophic syndrome improves after antiretroviral change, mostly after the switching of a protease inhibitor or stavudine with a nonnucleoside reverse transcriptase inhibitor (NNRTI) [12,13]. However, some reports associate lipodystrophic syndrome with NNRTI as well . Recent works have shown some association between the ApoC3 (−455) single nucleotide polymorphism (SNPs) and resistin and the development of the lipodystrophic syndrome, whereas others have reported that the carriage of the interleukin-1β (+3954) SNP protects against its presentation [15–17]. The potential role of the tumour necrosis factor (TNF)-α (−238) promoter SNP in HIV-related lipodystrophy has not been confirmed in recent studies [18–20].
Matrix metalloproteinases (MMPs) are a family of zinc-dependent endoproteases that share amino-acid sequences, structural domains and substrates and can degrade the extracellular matrix (ECM) proteins. Their activity depends on activation of MMPs zymogens and is influenced by tissue inhibitors of metalloproteinases (TIMPs) . MMPs are involved in the response to tissue injury and inflammation and their expression is induced by TNF-α and other cytokines, which are increased in serum of HIV-infected patients with lipodystrophic syndrome, considered as an inflammatory syndrome [17,22]. They are also amplifiers and regulators of the immune responses raised in infections . Because MMPs and their TIMPs are responsible for the turnover and degradation of connective-tissue proteins, they could be involved in the lipodystrophic syndrome pathogenesis as well. Some MMPs SNPs are associated with increased serum levels of MMPs. A SNP in the promoter of the MMP1 at −1607 bp (rs1799750), where an additional G residue creates an Ets binding site (5′GGAT3′ compared to 5′GAT3′) adjacent to an AP-1 site at −1602 bp, has been reported. The 2G a allele displays greater transcriptional activity than the 1G allele and has been linked to the incidence and progression of several cancers and is also associated with non-neoplastic diseases including infections such as osteomyelitis [24–27]. Antiretrovirals (ARVs), mostly protease inhibitors, have shown to inhibit the activity of some nuclear metaloproteases and therefore might contribute to the lipodystrophic syndrome pathogenesis [28–34].
Lipodystrophic syndrome continues to appear in ARV-treated HIV-infected patients, even with the modern thymidine-sparing regimen and its cause remains elusive. Because lipodystrophic syndrome's physical and metabolic consequences are so important for the patient, its genetic background, which could play a critical role in the lipodystrophic syndrome pathogenesis, merits further evaluation.
In the present study, we have analysed the incidence of lipodystrophic syndrome in 216 HIV-infected adult white patients on HAART and the associations among development of lipodystrophic syndrome, carriage of the (−16071G/2G) MMP1 promoter SNP and changes in serum levels of MMPs (1, 2, 3, 8, 9, 10, 13) and TIMPs (1, 2, 4).
HIV-infected patients followed at the HIV outpatient clinic of the Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain, were consecutively included in this cross-sectional study. All patients had documented HIV-1 infection, were at least 16 years old and had been taking HAART for at least 3 years at the time of enrolment in the study. Patients with adherence to ARV below 75% were excluded from the study. Patients receiving drugs with metabolic effects (such as steroids, androgens, thyroid hormones and antithyroid agents, ketoconazole, cytotoxic drugs and lipid-lowering agents) were also excluded.
Lipodystrophic syndrome diagnosis was based on body fat changes measured at the inclusion visit by a direct patient-self and doctor assessment, following a previously reported score, the Lipodystrophy Severity Grading Scale (LSGS) [4,35,36]. The degree of lipoatrophy and diffuse fat accumulation at each region was rated as absent (0 point), mild (noticeable on close inspection, one point), moderate (readily noticeable by patient/physician, two points) or severe (readily noticeable to a casual observer, three points). The overall score was the mean of the scores given by patient and physician. A clinical diagnosis of lipodystrophic syndrome was given to a patient with an overall score of 7 or higher. In addition, patients with severe fat changes in at least one body location were considered to have with lipodystrophic syndrome. LSGS has shown a good correlation with anthropometric and echographic lipodystrophic syndrome findings in a previous report of our group .
In addition, total dual absorptiometry [dual energy X-ray absorptiometry (DEXA)] of subcutaneous fat, considered the gold standard of lipodystrophic syndrome diagnosis, assessed using an Hologic QDR-4500 scanner (Hologic Inc., Weltham, Massachusetts, USA) was done in a subset of 55 individuals selected at random among the 216 HAART-treated HIV-infected patients studied, 34 with lipodystrophic syndrome (LSGS ≥ 7) and 21 without lipodystrophic syndrome (LSGS < 7). Lipodystrophic syndrome patients showed thinner subcutaneous leg fat measured by DEXA when compared with those without lipodystrophic syndrome (12.8 ± 5.9 vs. 18.6 ± 9.0%, P = 0.008). BMI was assessed in the 216 patients and other anthropometric parameters were measured in the 55 patients in whom fat DEXA was done as described elsewhere . Patients were members of a homogeneous population, all were white and residents of the same region (Asturias, northern Spain). Each participant gave informed consent for the study, which was approved by the Ethics Committee of the HUCA.
General metabolic assessments
CD4+ lymphocyte counts, HIV RNA viral load, glucose, total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterols, triglycerides (all measured after a 12-h overnight fast), renal and liver tests and other metabolic parameters were evaluated at study enrolment.
MMP1 genotypic analysis
Ten millilitres of blood from all HIV-infected patients was collected in a tube containing potassium EDTA. Genomic DNA was extracted from peripheral leukocytes following a salting-out method and was used in the PCR amplification reaction of the MMP1 promoter region as previously described .
Collection of sera
Matrix metalloproteinases and tissue inhibitors of metalloproteinases serum levels assessment
An additional 10 ml of whole blood was drawn from patients and centrifuged at 1800g for 5 min. The obtained serum was aliquoted in Eppendorf tubes and stored at −70°C until further use. MMPs (1, 2, 3, 8, 9, 10, 13) and TIMPs (1, 2, 4) were measured using the Quantibody Human MMP Array 1 from RayBiotech (Norcross, Georgia, USA) according to the manufacturer's instructions.
Quantitative demographic and analytical variables were compared at baseline between two groups with the t-test and Mann–Whitney test depending on their normal or non-normal distribution. Several groups were compared using one-way ANOVA and the Kruskal–Wallis tests according to the distribution and χ2-test was used for comparison of the qualitative variables. The χ2-test was also used to compare genotypic frequencies between the groups. Correlations were assessed with the Pearson's (normally distributed variables) and Spearman's (non-normally distributed variables) correlation coefficients. Logistic regression was used to determine the factors independently associated with lipodystrophic syndrome. All the reported P values were two-sided. A P value <0.05 was considered significant. The statistical analysis was performed with SPSS Software, version 16.0\9 SPSS, Chicago, Illinois, USA).
Two hundred and sixteen HIV-infected patients on HAART were recruited between July 2002 and July 2006. Patients were already on HAART for at least 36 months (mean 66.4 ± 36.1 months, range 36–144), had received ARVs previously in a pre-HAART era for an even longer period (mean 94.5 ± 43.4 months, range 36–210) and 105 (48.6%) of them were on or had received stavudine and 150 (69.4%) zidovudine. Patients on HAART received a combination of two nucleoside reverse transcriptase inhibitors in addition to one NNRTI [94 patients (43.5%): 53 on efavirenz and 41 on nevirapine] or to protease inhibitors [85 patients (39.4%): 36 on lopinavir, 26 on atazanavir, seven on saquinavir, six on nelfinavir, five on fosamprenavir, four on tipranavir, one on indinavir, all ritonavir-boosted except for nelfinavir] or were on other ARV combinations [37 patients (17.1%): 30 of whom were on abacavir as the third ARV). Eighty-two (38.0%) patients were diagnosed with lipodystrophic syndrome by the LSGS at study entry, 78 of whom (95.1%) had lipoatrophy, whereas 134 (62%) patients did not develop lipodystrophic syndrome.
Among the patients with lipodystrophic syndrome, 58 had been exposed to zidovudine at some time and 49 to stavudine. Only six patients with lipodystrophic syndrome and lipoatrophy had never been exposed to zidovudine or stavudine. All of them had been initially treated with didanosine combined with indinavir (four cases) and to full-dose ritonavir (two cases).
The 216 HIV-infected patients with and without lipodystrophic syndrome were stratified by clinical parameters including age, sex, hepatitis C virus (HCV) infection, AIDS diagnosis, nadir CD4 cell count, baseline HIV RNA load, duration of ARV therapy and HAART, and stavudine and zidovudine treatment (Table 1). A significant association was detected between lipodystrophic syndrome and having a diagnosis of AIDS (P = 0.03), lower nadir CD4 cells count (P = 0.02), absence of HCV infection (P = 0.04), longer duration of HAART (P = 0.003) or treatment with stavudine (P = 0.02). Lipodystrophic syndrome patients showed a significantly thinner thigh circumference (44.6 ± 4.4 vs. 48.2 ± 2.9 cm, P = 0.001) and slightly thinner arm (26.7 ± 3.9 vs. 28.2 ± 2.6 cm, P = 0.08) and waist circumferences (89.8 ± 5.8 vs. 92.8 ± 5.2 cm, P = 0.053) compared with those without lipodystrophic syndrome.
MMP1 genotypic study
The MMP1 (−16071G/2G) SNP was in Hardy–Weinberg equilibrium in the 212 HAART-treated HIV-infected patients with/without lipodystrophic syndrome genotyped for this SNP and in the lipodystrophic and non-lipodystrophic groups considered individually. The genotypic frequencies in these patients are described in Table 2. The frequency of 2G/2G genotype was significantly higher in the lipodystrophic syndrome group [41.3 vs. 20.5%, odds ratio (OR) 2.73 (95% confidence interval [CI] 1.41–5.29); χ2 = 9.62, P = 0.002 by the Yates correction test]. The carriage of the 2G allele was also more frequent among HIV-infected patients with lipodystrophic syndrome compared with those without lipodystrophic syndrome [96/160 (60.0%) vs. 132/264 (50.0%), OR 1.5 (95% CI 0.99–2.28); χ2 = 4.0, P = 0.046 by the Mantel–Haenszel test]. No differences were observed while comparing the genotypic and allelic frequencies of the MMP1 SNP between lipodystrophic syndrome patients with and without lipoatrophy. No significant differences among the different anthropometric measures between the different MMP1 genotypes were observed, although carriers of the 2G/2G genotype had thinner tricipital and abdominal skinfold thickness. No differences among the different metabolic parameters among the different MMP1 genotypes were found (Table 2).
Matrix metalloproteinases and tissue inhibitors of metalloproteinases serum levels
HIV-infected patients with and without lipodystrophic syndrome had similar levels of serum MIPs and TIMPs, but higher serum levels of MMP1 and lower levels of TIMP4 than those with lipodystrophic syndrome (Table 3). No significant differences in serum MMPs and TIMPs were observed between those with and without lipoatrophy except for MMP8. The different correlations among MMPs, TIMPs and metabolic and anthropometric parameters are shown in Table 4.
Carriers of the 2G/2G mutated genotype had significantly higher serum levels of MMP1 compared with those with the 1G/1G wild-type genotype (14.0 ± 20.1 vs. 9.6 ± 14.1 ng/ml, P = 0.02). Those with the 1G/2G genotype also had higher serum levels of MMP1 compared with carriers of the 1G/1G genotype, although without reaching statistical significance (15.1 ± 41.5 vs. 9.6 ± 14.1 ng/ml, P = 0.3). After excluding carriers of the 2G allele, no significant differences were observed in MMP1 serum levels between those with and without lipodystrophic syndrome (9.1 ± 5.9 vs. 10.1 ± 17.8 ng/ml, P = 0.2). When comparing the lipodystrophic syndrome-enhancing effect of the carriage of the MMP1 SNP on HIV-infected patients treated with stavudine with that on HIV-infected patients without stavudine, we found the effect to be significantly more evident in those without stavudine (P = 0.005 vs. P = 0.18). No significant differences were observed in serum levels of MMP9 between the 85 HAART-treated patients with protease inhibitors and the 131 without protease inhibitors (292.4 ± 287.0 vs. 325.9 ± 306.0 ng/ml, P = 0.25) or in other MMPs or TIMPs (data not shown). No differences were observed while comparing the MMPs and TIMPs serum levels of HAART-treated patients on different protease inhibitors. Likewise, no differences were observed while comparing MMPs and TIMPs serum levels of HAART-treated patients on protease inhibitors with those on efavirenz, nevirapine or other ARV regimens.
Using logistic regression to study the variables that were associated with lipodystrophic syndrome, it was found that carriage of the MMP1 2G allele, lower serum levels of TIMP4, absence of HCV coinfection and treatment with stavudine or zidovudine were the only variables independently associated with lipodystrophic syndrome. When considering only lipoatrophy, the carriage of the MMP1 2G allele, lower serum levels of TIMP4, higher serum levels of MMP3, absence of HCV coinfection, treatment with stavudine and time on zidovudine were the only variables independently associated with this presentation (Table 5).
In this study, we report for the first time that the carriage of the 2G/2G genotype of the MMP1 (−16071G/2G) SNP associates with the presence of lipodystrophic syndrome in HIV-infected patients on HAART. This enhancing effect might be mediated by the significantly increased serum levels of MMP1 found in the lipodystrophic syndrome patients carriers of this MMP1 genotype. In addition, TIMP4 serum levels were significantly lower in lipodystrophic syndrome patients compared with those without lipodystrophic syndrome. Similar results were observed when considering only lipoatrophic patients. Lipodystrophic syndrome was strongly associated with MMP1 SNP carriage, and also with lower TIMP4 serum levels, treatment with stavudine and zidovudine and absence of HCV coinfection by multivariate logistic regression.
MMPs are upregulated in some infections such as hepatitis B, endotoxin shock, Helicobacter pylori, Mycobacterium tuberculosis, and also HIV . Their levels are increased in different infections because they are amplifiers and regulators of the immune responses induced by them. MMPs, which play a leading role in ECM remodelling and degradation, are involved in adipocyte differentiation as well, a process important in lipodystrophic syndrome pathogenesis, especially MMP2 and MMP9 [30,37]. Interestingly, between HAART-treated patients with and without lipodystrophic syndrome, we could not find differences in MMP2 or MMP9 serum levels, however, there were differences in serum levels of MMP1, a collagenase that degrades type I and II fibrilar collagens. MMP1 activity is inhibited, in addition to TIMP1, by YKL-40, a major protein secreted by stromal vascular fraction cells of the visceral adipose tissue . It might be postulated that the decreased body fat in lipodystrophic syndrome patients could induce a reduced YKL-40 production and indirectly increase MMP1 activity, which loses its YKL-40 blockade. This hypothesis is plausible in our lipodystrophic syndrome cohort, composed mostly of lipoatrophic individuals. This might be even more evident in carriers of the 2G/2G genotype of MMP1 SNP in whom MMP1 serum levels were already higher than in carriers of the 1G/1G genotype. An increased MMP1 activity might degrade more ECM, a biological framework necessary for adipose tissue differentiation, making lipodystrophic syndrome more severe in those carriers of the MMP1 SNP. Lipodystrophic syndrome was more frequent in those patients with the 2G/2G MMP1 genotype compared with those with other genotypes suggesting a dosing effect of this SNP. The MMP1 promoter 2G allele is a genetic polymorphism that exists at a high allele frequency of 80–90% in the general population. It might be a hereditary trait that is shared among races. The 2G/2G carriage was observed in 28.4% in the HIV-infected patients analysed in our study and in 33.7% of the HUCA Caucasian Blood Bank donors genotyped for this MMP1 SNP elsewhere . Therefore, the MMP1 2G/2G genotype might be recognized as an essential genetic precondition for the development of lipodystrophic syndrome. Ours is the first report in which an association between MMPs and lipodystrophic syndrome has been described in the world literature. However, other genetic SNPs might play a role in lipodystrophic syndrome pathogenesis as well. The fact that there were no differences in MMP1 serum levels in lipodystrophic syndrome patients after excluding those with the MMP1 2G allele in our cohort could suggest a different pathogenic mechanism of lipodystrophic syndrome for those with the MMP1 SNP and those without it. Recent work has shown an association between BMI and the MMP1 SNP in Koreans aged over 50 years, a finding we did not observe in our only white cohort that was slightly younger than the Korean population .
It is more difficult to explain the mechanisms by which HAART therapy might induce lipodystrophic syndrome through MMPs. Latronico et al. have reported that ARVs can reduce the capacity of peripheral blood mononuclear cells of HIV-infected patients to secrete increased amounts of MMP9. In in vitro experiments, it was also shown that some protease inhibitors (saquinavir and nelfinavir) reduce the human adipocyte differentiation process by MMP9 blockade [29,30]. Other protease inhibitors (ritonavir, lopinavir and atazanavir) interfere with the processing of lamin A/C, a component of the nuclear lamina by inhibition of the MP ZMPSTE24 [31,32]. Both protease inhibitors' blocking mechanisms could contribute to lipodystrophic syndrome pathogenesis. However, HAART-treated patients with and without lipodystrophic syndrome had similar MMP9 serum levels. In addition, we could not find differences in MMP serum levels between those on protease inhibitors and NNRTI-based regimens. Furthermore, no differences were observed among the different protease inhibitors used, although there were no patients on darunavir in our study, a protease inhibitor recently introduced in clinic that does not inhibit ZMPSTE24, although this is a metalloproteinase that cleaves prelamin A to lamin A at the nuclear membrane level not ECM . The unpublished blocking effect of both NNRTIs, efavirenz and nevirapine, on MMP activity might explain in part the unexpectedly higher association of efavirenz with lipoatrophy when compared with lopinavir/ritonavir both in combination with thymidine nucleosides shown in the ACTG 5142 study . In addition, efavirenz was shown to impair adipogenesis in a higher extension than lopinavir/ritonavir in in vitro experiments. In this adipogenesis blocking effect, mitochondrial toxicity was not involved .
The MMP1 SNP might associate with other lipodystrophic syndrome-enhancing SNPs already reported, such as those in the Apo C3 (−455)  and resistin . An association of different lipodystrophic syndrome-enhancing SNPs could enhance its earlier presentation, mostly but not exclusively, induced by thymidine analogues such as stavudine, the more lipodystrophic syndrome-enhancing ARV, or zidovudine, whereas some other SNPs could protect against lipodystrophic syndrome . Our results confirm the role of stavudine in the appearance of lipodystrophic syndrome. Interestingly, the lipodystrophic syndrome-enhancing effect of the MMP1 SNP was more evident in those patients without stavudine in our cohort. This fact gives even more value to our observation of the potential role of the MMP1 SNP in stavudine-free patients on lipodystrophic syndrome pathogenesis. Our data show a protective effect of HCV coinfection against lipodystrophic syndrome presentation, a rather controversial observation but recently confirmed by the large multicentre FRAM study [41–43].
Although caution is needed due to the relatively small number of our only white cohort and larger populations of other ethnic backgrounds must be genotyped for this mutation, our results suggest that genotyping the (−16071G/2G) MMP1 gene SNP could be helpful for the evaluation of the risk of developing lipodystrophic syndrome, mostly lipoatrophy, and for tailoring ARV therapy to each patient's risk avoiding stavudine, zidovudine and other thymidine analogues in carriers of this MMP1 SNP. In addition, more studies to determine more precisely the role of MMPs and their HAART-induced serum level changes on lipodystrophic syndrome pathogenesis are needed.
The study was supported by a FEDER grant [SAF2007-64566] given to V.A. DEXA studies were done by Abbott Virology, Spain.
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