José M Gallego-Escuredo

University of Barcelona, Barcino, Catalonia, Spain

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Publications (17)74.71 Total impact

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    ABSTRACT: Objective:Fibroblast growth factor (FGF)-21 and possibly FGF19, protect against type 2 diabetes mellitus (T2DM) and obesity in rodents. We investigated the circulating levels of FGF21 and FGF19 in obese patients with varying degrees of abnormal glucose homeostasis, and we determined gene expression for FGF receptors (FGFR1-4) and the co-receptor β-Klotho, in liver and adipose tissues.Subjects and methods:We analyzed 35 lean healthy (71% men) and 61 obese patients (49% men, median BMI: 40.5 kg/m(2), interquartile range: 34.7-46.2). Among obese patients, 36 were normoglycemic, 15 showed impaired glucose tolerance and 10 had T2DM. Biopsies from liver and visceral and subcutaneous fat from a subset of obese patients and controls were analyzed. FGF19 and FGF21 levels were measured using ELISA, and tissue mRNA and protein levels by RT-PCR and immunoblotting.Results:FGF21 serum levels were significantly increased in obese patients compared to controls (P<0.001), whereas FGF19 levels were decreased (P<0.001). FGF21 levels were positively correlated with HOMA-R (P=0.0002, r=0.37) and insulin (P=0.001, r=0.32), whereas FGF19 levels were negatively correlated (P=0.007, r=-0.27; P=0.003, r=-0.28; respectively). After adjusting for BMI, the correlations of FGF21 and FGF19 levels with indicators of abnormal glucose homeostasis were not significant. In obese patients, the hepatic expression of FGF21 was increased. (P=0.04). β-Klotho transcript levels in visceral fat (P=0.002) and β-Klotho protein levels in subcutaneous (P=0.03) and visceral fat (P=0.04) were significantly reduced in obese patients, whereas hepatic levels for β-Klotho (P=0.03), FGFR1 (P=0.04) and FGFR3 (P=0.001) transcripts were significantly increased.Conclusions:Obesity is characterized by reciprocal alterations in FGF19 (decrease) and FGF21 (increase) levels. Although worsened in diabetic obese patients, obesity itself appears as the predominant determinant of the abnormalities in FGF21 and FGF19 levels. Opposite changes in β-Klotho expression in fat and liver indicate potential tissue-specific alterations in the responsiveness to endocrine FGFs in obesity.International Journal of Obesity accepted article preview online, 12 May 2014; doi:10.1038/ijo.2014.76.
    International journal of obesity (2005) 05/2014; · 5.22 Impact Factor
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    ABSTRACT: Conflicting reports on the effects of efavirenz (EFV) and lopinavir/ritonavir (LPV/r) on subcutaneous adipose tissue (SAT) have been described. To assess the 48-week molecular and clinical effects of LPV/r and EFV, combined with tenofovir/emtricitabine (TDF/FTC), on SAT of HIV-infected, antiretroviral-naïve patients. Forty-four adults were started with LPV/r or EFV combined with TDF/FTC. Fasting metabolic tests, HIV RNA, CD4 cell count, and fat measured by dual X-ray absorptiometry (DEXA) scans were obtained at study entry and week 48. Mitochondrial DNA (mtDNA) and transcripts for mtDNA-encoded proteins and genes involved in inflammation, adipocyte differentiation and metabolism were assessed in paired SAT biopsies. Whole body fat and limb fat mass increased in the LPV/r and EFV groups. MtDNA and Cox II did not change and cytochrome b increased significantly in EFV patients. TNF-α and MCP-1 gene expression did not change in the LPV/r group, but significantly increased in the EFV group. IL-18 decreased in LPV/r group while it increased in EFV group. Starting TDF/FTC plus EFV was associated with increased expression of genes encoding for inflammatory cytokines in SAT in naïve patients. Therapy with TDF/FTC plus LPV/r or EFV was associated with an increase in subcutaneous fat mass.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 05/2014; · 4.65 Impact Factor
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    ABSTRACT: HIV-1/HAART-associated lipodystrophy syndrome (HALS) has been associated with exposure to stavudine (d4T) through mitochondrial dysfunction. We performed a 48-week study to assess the effects of switching from d4T to raltegravir (RAL) on metabolic and fat molecular parameters of patients with HALS. Forty-two patients with HALS and a median exposure to d4T > 7 years were switched to RAL and followed for 48 weeks. Fasting metabolic tests, HIV RNA, CD4 cell count, and fat measured by DEXA were obtained at baseline and week 48. mtDNA and gene transcripts for PPAR gamma, adiponectin, cytochrome b, Cox IV, TNF alpha, MCP-1 and CD68 were assessed in paired subcutaneous fat tissue biopsies. Lipid parameters, fasting glucose, insulin, and HOMA-IR did not change significantly. Whole body fat (P = 0.0027) and limb fat mass (P<0.0001) increased from baseline. Trunk/limb fat ratio (P = 0.0022), fat mass ratio (P = 0.0020), fat mass index (P = 0.0011) and percent leg fat normalized to BMI (P<0.0001) improved after 48 weeks. Relative abundance of mtDNA, expression of PPAR gamma, adiponectin, Cyt b, and MCP-1 genes increased, whereas Cox IV, TNF alpha, and CD68 did not change significantly from baseline. Switching from d4T to RAL in patients with HALS is associated with an increase in limb fat mass and an improvement in markers of adipocyte differentiation and mitochondrial function in SAT.
    PLoS ONE 01/2014; 9(2):e89088. · 3.73 Impact Factor
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    ABSTRACT: OBJECTIVE:: Lipodystrophy in HIV-1-infected, antiretroviral-treated-patients is often associated with opposite alterations in adipose tissue depots: lipoatrophy of subcutaneous adipose tissue (SAT) versus lipohypertrophy of visceral adipose tissue (VAT). We determined the specific molecular alterations in VAT relative to SAT in patients. DESIGN:: We analyzed the expression of marker genes of mitochondrial function, adipogenesis and inflammation in a unique collection of eight biopsies of omental VAT from HIV-1-infected, antiretroviral-treated patients with lipodystrophy. For comparison, we analyzed SAT from ten patients, and SAT and VAT from ten non-infected individuals. METHODS:: Quantitative real-time PCR of mitochondrial DNA and gene transcripts; immunoblot and multiplex for quantification of specific proteins. RESULTS:: Similar mitochondrial DNA depletion and abnormal increases in mitochondrial protein levels were found in VAT and SAT from patients. Transcript levels of adipogenesis and metabolism marker genes were unaltered in VAT, but were decreased in SAT. TNFα and CD68 were similarly induced in both adipose depots from patients, but other markers of inflammation-related pathways showed distinct alterations: interleukin-18 and IL1RN were induced only in SAT, whereas interleukin-6, -8 and MCP-1 expression was reduced in VAT but not in SAT. CONCLUSIONS:: Mitochondrial alterations are similar in VAT and SAT from patients whereas adipogenic gene expression is decreased in SAT but unaltered in VAT, highlighting the relevance of adipogenic processes in the differential alterations of fat depots. Specific disturbances in inflammatory status in VAT relative to SAT are present. Milder induction of pro-inflammatory signaling in VAT could be involved in preventing fat wasting in this depot.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 05/2013; · 4.65 Impact Factor
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    ABSTRACT: BACKGROUND: Facial lipoatrophy, a common alteration among HIV-1-infected, antiretroviral-treated patients, is often corrected using autologous transplantation. In some cases, especially when enlarged adipose tissue from the dorso-cervical area (i.e. a "buffalo hump") is used as a source of fat for transplantation, the transplanted fat develops progressive hypertrophy. To gain insight into the molecular basis of this phenomenon, we evaluated the cell morphology and gene expression in this hypertrophied facial fat. METHODS: Quantitative real-time polymerase chain reaction was used to examine the expression of various marker genes in a sample of facial fat that underwent hypertrophy after autologous transplantation. The results were compared with gene expression data from "buffalo hump" fat and subcutaneous fat from healthy controls. Optical and electron microscopic analyses were used to determine cell morphology. RESULTS: The enlarged facial adipose tissue did not exhibit the overt microscopic morphology of brown adipose tissue but (similar to "buffalo hump" fat) it contained adipocytes heterogeneous in size. The enlarged facial fat retained the partial molecular signature of a distorted brown-to-white adipocyte phenotype, including expression of uncoupling protein-1 (UCP1) transcript, an showed the unaltered unaltered adipogenesis and inflammation that are characteristic of "buffalo hump" fat. CONCLUSIONS: Despite being implanted in a former lipoatrophic area, facially grafted "buffalo hump" tissue appears to retain the altered phenotype of dorso-cervical adipose cells, thus accounting for its progressive enlargement. These results argue that caution should be exercised when considering "buffalo hump" fat depots as a fat source for autologous transplantation.
    Antiviral therapy 01/2013; · 3.07 Impact Factor
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    ABSTRACT: Objective In rodents, brown (BAT) and white (WAT) adipose tissues are targets and expression sites for fibroblast growth factor-21 (FGF21). In contrast, human WAT expresses negligible levels of FGF21. We examined FGF21 expression in human BAT samples, including the induced BAT found in adult patients with pheochromocytoma, and interscapular and visceral BAT from newborns. Methods The expression of FGF21 and uncoupling protein-1 (UCP1, a brown adipocyte marker), was determined by quantitative real-time-PCR and immunoblotting. The transcript levels of marker genes for developmentally-programmed BAT (zinc-finger-protein of the cerebellum-1, ZIC1) and inducible-BAT (cluster of differentiation-137, CD137) were also determined. Results FGF21 and UCP1 are significantly expressed in visceral adipose tissue from pheochromocytoma patients, but not in visceral fat from healthy individuals. In neonates, FGF21 and UCP1 are both expressed in visceral and interscapular fat, and their expression levels show a significant positive correlation. Marker gene expression profiles suggest that inducible BAT is present in visceral fat from pheochromocytoma patients and neonates, whereas developmentally-programmed BAT is present in neonatal interscapular fat. Conclusions Human BAT, but not WAT, expresses FGF21. The expression of FGF21 is especially high in inducible, also called beige/brite, neonatal BAT, but it is also found in the interscapular, developmentally-programmed, BAT of neonates
    Metabolism: clinical and experimental 01/2013; · 3.10 Impact Factor
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    ABSTRACT: BACKGROUND:: To determine the role of fibroblast growth factor (FGF)-19 and FGF21 and the endocrine FGFs receptor system in the metabolic alterations that manifest in HIV-1-infected patients undergoing highly active antiretroviral treatment (HAART). METHODS:: Serum FGF19 and FGF21 levels were determined in 4 groups of individuals as follows: (1) HIV-1-infected HAART patients with lipodystrophy (n = 38); or (2) without lipodystrophy (n = 34); (3) untreated (naive) HIV-1-infected patients (n = 34); and (4) healthy controls (n = 31). Serum FGF19 levels were correlated with anthropometric, metabolic, HIV-1 infection-related, and HAART-related parameters and with FGF21 levels. The gene expression of FGF receptor 1 and the coreceptor β-Klotho was analyzed in adipose tissue from 10 individuals from each group. RESULTS:: Serum FGF19 levels were significantly reduced in all groups of HIV-1-infected patients, whereas FGF21 levels were increased. FGF19 levels were negatively correlated with insulin resistance and insulin levels and positively correlated with high-density lipoprotein cholesterol. FGF19 was inversely correlated with cumulative exposure to nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor drugs. The expression of FGF receptor 1 and coreceptor β-Klotho was reduced in adipose tissue from all groups of HIV-infected patients. CONCLUSIONS:: FGF19 levels are reduced in HIV-1-infected patients, in contrast with FGF21 levels. Impaired expression of the corresponding receptor and coreceptor, which mediate the actions of endocrine FGFs in adipose tissue, suggests a resistance to the metabolic effects of FGF19 and FGF21 in HIV-1-infected patients. Considering the beneficial effects of endocrine FGFs on metabolism, the observed reduction in FGF19 levels and decreased sensitivity to endocrine FGFs in adipose tissue may contribute to metabolic alterations in HIV-1-infected patients.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 12/2012; 61(5):527-534. · 4.65 Impact Factor
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    ABSTRACT: : HIV-1 can induce disturbances in adipose tissue in infected subjects through the effects of some of its proteins or inflammation. It is not known whether this also takes place in HIV-1-infected long-term nonprogressors (LTNPs). Our objectives were to determine whether adipocyte differentiation/lipid, inflammatory, and mitochondrial parameters are perturbed in abdominal wall subcutaneous adipose tissue of untreated HIV-1-infected patients LTNPs. : Cross-sectional study involving 10 LTNPs, 10 typical progressors (TPs), and 10 uninfected controls (UCs). The parameters assessed were peroxisome proliferator-activated receptor-gamma (PPARγ), lipoprotein lipase, and fatty acid-binding protein 4 mRNA (adipogenic/lipid); tumor necrosis factor-alpha, interleukin 18 (IL-18), β2-MCG, monocyte chemoattractant protein 1, CD1A, and C3 mRNA (inflammation); and cytochrome c oxidase subunit II (COII), COIV, CYCA, nuclear respiratory factor 1, PPARγ coactivator 1α mRNA, and mtDNA content (mitochondrial). : Regarding adipogenic/lipid parameters, LTNPs had PPARγ, lipoprotein lipase, and fatty acid-binding protein 4 mRNA significantly decreased compared with UCs (P ≤ 0.001 for all comparisons). PPARγ mRNA was significantly greater in LTNP than in TP (P = 0.006). With respect to inflammatory parameters, tumor necrosis factor-alpha, IL-18, and β2-MCG mRNA were significantly higher in LTNPs compared with UCs (P < 0.005 for all comparisons), whereas IL-18 mRNA was greater in TPs compared with LTNPs (P = 0.01). As mitochondrial parameters are concerned, mtDNA was significantly reduced in LTNPs compared with TPs (P = 0.04) and UCs (P = 0.03). COII and COIV were also significantly reduced in LTNPs compared with UCs and TPs. : Adipose tissue from untreated LTNPs may have limited but significant derangements in some adipogenic/lipid and may have inflammatory processes at a lower degree than that observed in untreated TPs. LTNPs may have mitochondrial-related alterations in adipose tissue which are greater than that observed in TPs.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 05/2012; 61(2):131-7. · 4.65 Impact Factor
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    ABSTRACT: Type 2 familial partial lipodystrophy (FPLD2) is a rare adipose tissue (AT) disease caused by mutations in LMNA, in which lipomas appear occasionally. In this study, we aimed to histologically characterize FPLD2-associated lipomatosis and study the expression of genes and proteins involved in cell cycle control, mitochondrial function, inflammation and adipogenesis. One lipoma and perilipoma fat from each of four subjects with FPLD2 and 10 control subjects were analysed by optical microscopy. The presence of inflammatory cells was evaluated by immunohistochemistry. Real-time RT-PCR and Western blot were used to evaluate gene and protein levels. Adipocytes from lipodystrophic patients were significantly larger than those of controls, in both the lipomas and perilipoma fat. Lipodystrophic AT exhibited CD68(+) macrophages and CD3(+) lymphocytes infiltration. TP53 expression was reduced in all types of lipomas. At protein level, C/EBPβ, p53 and pRb were severely disturbed in both lipodystrophic lipomas and perilipoma fat coming from lipoatrophic areas, whereas the expression of CEBPα was normal. Mitochondrial function genes were less expressed in lipoatrophic fat. In both lipomas and perilipoma fat from lipoatrophic areas, the expression of adipogenes was lower than controls. Even in lipomas, the adipogenic machinery is impaired in lipodystrophic fat coming from lipoatrophic regions in FPLD2, although the histological phenotype is near-normal, exhibiting low-grade inflammatory features. Our results suggest that the p53 pathway and some adipogenic proteins, such as CEBPα, could contribute to the maintenance of this near normal phenotype in the remnant AT present in these patients.
    Clinical Endocrinology 08/2011; 76(6):816-24. · 3.40 Impact Factor
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    ABSTRACT: The non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine and efavirenz are drugs of choice for initial antiretroviral treatment for HIV-1 infection. Although NNRTIs have not traditionally been associated with the appearance of adipose alterations, recent data suggest that efavirenz may contribute to adipose tissue alterations in antiretroviral-treated patients, consistent with its ability to impair differentiation of adipocytes in cell cultures. No such effects have been reported for nevirapine, the other most commonly used NNRTI. In this study, we determined the effects of nevirapine on differentiation, gene expression and release of regulatory proteins (adipokines and cytokines) in differentiating human adipocytes, and compared them with those of efavirenz. Efavirenz caused a dose-dependent repression of adipocyte differentiation that was associated with down-regulation of the master adipogenesis regulator genes SREBP-1, PPARγ and C/EBPα, and their target genes encoding lipoprotein lipase, leptin and adiponectin, which are key proteins in adipocyte function. In contrast, nevirapine does not affect adipogenesis and causes a modest but significant coordinate increase in the expression of SREBP-1, PPARγ and C/EBPα and their target genes only at a concentration of 20 μM. Whereas efavirenz caused a significant increase in the release of pro-inflammatory cytokines (interleukin [IL]-8, IL-6, monocyte chemoattractant protein-1), plasminogen activator inhibitor type-1 and hepatocyte growth factor (HGF), nevirapine either had no effect on these factors or decreased their release (IL-6 and HGF). Nevirapine significantly increased adiponectin release, whereas efavirenz strongly repressed it. Moreover, nevirapine inhibited preadipocyte endogenous reverse transcriptase activity, whereas efavirenz did not alter it. It is concluded that, in contrast with the profound anti-adipogenic and pro-inflammatory response elicited by efavirenz, nevirapine does not impair adipogenesis.
    Antiviral research 05/2011; 91(2):112-9. · 3.61 Impact Factor
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    ABSTRACT: HIV-1-infected patients with lipodystrophy show insulin resistance, dyslipidemia and other signs of metabolic syndrome. Fibroblast growth factor-21 (FGF21) is a novel metabolic regulator that has been suggested to exert beneficial effects on metabolic homeostasis and insulin sensitivity. Our goal was to determine the relationship between FGF21 levels and metabolic alterations in these patients. Serum FGF21 levels were analyzed in 179 individuals belonging to four groups: HIV-1-infected, antiretroviral-treated patients that have developed lipodystrophy (n = 59); HIV-1-infected, antiretroviral-treated patients without lipodystrophy (n = 45); untreated (naive) HIV-1-infected patients (n = 41); and healthy control individuals (n = 34). Serum FGF21 levels were correlated with parameters indicative of altered fat distribution, metabolic and cardiovascular risk, and in relation to HIV-1 infection and antiretroviral treatment regimens. Serum FGF21 levels were increased in all HIV-1-infected patients, but the increases were most marked in those with lipodystrophy. FGF21 levels showed a strong positive correlation with indicators of lipodystrophy (trunk/apendicular fat ratio, waist-to-hip ratio), insulin resistance (fasting glucose, HOMA-R), dyslipidemia (low-density lipoprotein cholesterol), and liver injury (γ-glutamyltransferase). FGF21 levels are increased in HIV-1-infected patients, especially in those with lipodystrophy, and this increase is closely associated with insulin resistance, metabolic syndrome and makers of liver damage. Further research will be required to determine whether the increase in FGF21 levels is caused by a compensatory response or resistance to FGF21, and to establish the potential of FGF21 as a biomarker of altered metabolism in HIV-1-infected, antiretroviral-treated patients.
    AIDS (London, England) 10/2010; 24(17):2629-37. · 4.91 Impact Factor
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    ABSTRACT: The development of efficacious antiretroviral drugs that minimize adverse effects is a current challenge in HIV-1 therapy. Metabolic alterations reminiscent of the metabolic syndrome and overt lipodystrophy appear often in HIV-1-infected patients undergoing antiretroviral treatment. The etiopathogenesis of these alterations is complex, but lipotoxicity has recently emerged as a key concept for explaining the metabolic syndrome in HIV-1-infected patients, similarly to what has been observed in diseases such as obesity and genetic lipodystrophies. Antiretroviral drugs from distinct drug families may directly elicit such lipotoxic phenomena, via increased lipolysis, enhanced adipocyte apoptosis and impaired adipogenesis, which collectively lead to a reduced capacity of subcutaneous adipose tissue to enlarge to meet fat storage requirements. Thus, fatty acids that cannot be properly stored as triglycerides in subcutaneous adipose tissue are expected to accumulate in visceral fat as well as in organs and tissues, such as the pancreas, muscle and liver, leading to the pattern of metabolic alterations associated with abnormal ectopic fat accumulation, mainly insulin resistance. Inflammatory responses, evoked by the combined effects of antiretroviral drugs and the underlying HIV-1 infection, also contribute to lipotoxicity, reflecting the action of pro-inflammatory cytokines that enhance lipolytic activity in adipose tissue and impair adipogenesis. Minimizing the lipotoxic action of antiretroviral drugs is ultimately essential in reducing metabolic alterations in treated patients. Moreover, pharmacological strategies that reduce lipotoxicity and promote adipose tissue expandability can be expected to ameliorate the overall metabolic abnormalities in HIV-1-infected, antiretroviral-treated patients.
    Current pharmaceutical design 10/2010; 16(30):3371-8. · 4.41 Impact Factor
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    ABSTRACT: In the present study, a comparative assessment of the effects of efavirenz (EFV) and lopinavir/ritonavir (LPV/r; 4:1) on human adipocytes in culture has been performed. Human pre-adipocytes were treated with EFV or LPV/r during or after adipogenic differentiation. Acquisition of adipocyte morphology, expression of gene markers of mitochondrial toxicity, adipogenesis and inflammation, and release of adipokines and cytokines to the medium were measured. Results indicated that EFV and LPV/r impaired adipocyte differentiation in association with a reduction in transcript levels for adipogenic differentiation genes (adiponectin, lipoprotein lipase, leptin) and master regulators of adipogenesis (PPAR, C/EBP). The effects were greater with EFV than LPV/r. Both LPV/r and EFV induced increases in monocytechemoattactant protein-1 (MCP-1) mRNA levels, but the effect was greater with EFV. Similarly, the release of proinflammatory cytokines and other inflammation-related molecules (interleukins 6 and 8, MCP-1, PAI-1) was enhanced to a much higher degree by EFV than by LPV/r. Adiponectin and leptin release by adipocytes was reduced by both drugs, although to a higher extent by EFV. Neither drug affected mitochondrial DNA levels, transcripts encoding mitochondrial proteins or lactate release by adipocytes. In previously differentiated adipocytes, EFV caused a significant reduction in PPARγ and adiponectin expression, whereas LPV/r did not. We conclude that both EFV and LPV/r impair human adipogenesis, reduce adipokine release and increase the expression and release of inflammation-related cytokines, but the overall effects are greater with EFV. These findings may have implications for the pathogenesis of HIV-1-associated lipodystrophy and the development of HIV-1 therapies.
    Current HIV research 10/2010; 8(7):545-53. · 1.98 Impact Factor
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    ABSTRACT: Although antiretroviral therapy improves immune response, some human immunodeficiency virus-infected patients present unsatisfactory CD4 T cell recovery despite achieving viral suppression, resulting in increased morbidity and mortality. Cross-sectional, case-control study to characterize the mechanism and to identify predictive factors of poor immune response. We included 230 patients who were receiving highly active antiretroviral therapy and who had a viral load <50 copies/mL for >2 years; 95 were "discordant" (case patients; CD4 T cell count always <350 cells/microL), and 135 were "concordant" (control subjects). Activation markers, CD4 T cell death (necrosis, intrinsic apoptosis, and extrinsic apoptosis), and caspase-3 were measured. Clinical parameters, particularly antiretroviral combinations, were correlated with immune recovery. Discordant patients showed higher levels of activation markers, mainly in CD4 T cells (p < .001), and higher rates of spontaneous cell death (P < .001). Rates of activation and rates of CD4 T cell death (mainly by intrinsic apoptosis) were the best predictive factors for immune recovery, along with nadir CD4 T cell count. Patients who were receiving a protease inhibitor-based regimen were more likely to be discordant and showed higher rates of activation (P= .011), higher rates of CD4 T cell death (P = .033), and a lower nadir CD4 T cell count (P < .001). Multivariate analysis, however, ruled out any effect of protease inhibitors on immune recovery. No differences were observed between the use of tenofovir-emtricitabine (Truvada) and the use of abacavir-lamivudine (Kivexa). CD4 T cell apoptosis by the intrinsic pathway represents the determinant mechanism of the unsatisfactory immune recovery and should be targeted to manage therapy for discordant patients. The predictive value of low nadir CD4 T cell count for a poor immune recovery led us to consider starting antiretroviral therapy earlier. No differences were observed among antiretrovirals in terms of immune recovery.
    Clinical Infectious Diseases 05/2010; 50(9):1300-8. · 9.37 Impact Factor
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    ABSTRACT: Uridine has been advocated for the treatment of HIV-1/HAART-associated lipodystrophy (HALS), although its metabolism in HIV-1-infected patients is poorly understood. Plasma uridine concentrations were measured in 35 controls and 221 HIV-1-infected patients and fat uridine in 15 controls and 19 patients. The diagnosis of HALS was performed following the criteria of the Lipodystrophy Severity Grading Scale. Uridine was measured by a binary gradient-elution HPLC method. Analysis of genes encoding uridine metabolizing enzymes in fat was performed with TaqMan RT-PCR. Median plasma uridine concentrations for HIV-1-infected patients were 3.80 µmol/l (interquartile range: 1.60), and for controls 4.60 µmol/l (IQR: 1.8) (P = 0.0009). In fat, they were of 6.0 (3.67), and 2.8 (4.65) nmol/mg of protein, respectively (P = 0.0118). Patients with a mixed HALS form had a median plasma uridine level of 4.0 (IC95%: 3.40-4.80) whereas in those with isolated lipoatrophy it was 3.25 (2.55-4.15) µmol/l/l (P = 0.0066). The expression of uridine cytidine kinase and uridine phosphorylase genes was significantly decreased in all groups of patients with respect to controls. A higher expression of the mRNAs for concentrative nucleoside transporters was found in HIV-1-infected patients with respect to healthy controls. HIV-1 infection is associated with a decrease in plasma uridine and a shift of uridine to the adipose tissue compartment. Antiretroviral therapy was not associated with plasma uridine concentrations, but pure lipoatrophic HALS was associated with significantly lower plasma uridine concentrations.
    PLoS ONE 01/2010; 5(11):e13896. · 3.73 Impact Factor
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    ABSTRACT: Mitochondrial damage of HIV and antiretrovirals, especially nucleoside-analogue interference on mitochondrial DNA (mtDNA) replication, is reported to underlay highly active antiretroviral therapy (HAART)-related hyperlactatemia, but scarce approaches have been performed to correlate clinical manifestations and mitochondrial abnormalities. We obtained lymphocytes and monocytes of 26 HIV-infected and treated patients who developed hyperlactatemia and after recovery, 28 nonhyperlactatemic HIV subjects on HAART, 31 naive individuals, and 20 uninfected controls. Mitochondrial replication and transcription analysis were performed by quantitative real-time PCR, mitochondrial translation quantification by western blot and mitochondrial enzymatic activities by spectrophotometry. Mitochondrial parameters decreased during hyperlactatemia and improved at recovery. Mitochondrial replication and transcription species were reduced (P = 0.16 and P = 0.71), but the most significant decay was observed on mitochondrial protein content (P < 0.05) and mitochondrial complexes III and IV activities (P < 0.01 and P < 0.001). During hyperlactatemia lactate level correlated complexes III and IV function (P < 0.05). After recovery mitochondrial parameters achieved values of nonhyperlactatemic HIV individuals, which were lower than ranges of naive subjects and uninfected controls. HIV and HAART-related hyperlactatemia is associated with a general mitochondrial impairment which reverts after recovery. Mitochondrial biochemistry show a better correlation with lactate levels than mitochondrial genetics suggesting that mitochondrial function could be a better marker of hyperlactatemia development than mtDNA content.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 09/2009; 52(4):443-51. · 4.65 Impact Factor
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    ABSTRACT: To elucidate the molecular basis of the progressive enlargement of dorso-cervical adipose tissue, the so-called 'buffalo hump', that appears in a sub-set of patients with HIV-1/HAART-associated lipodystrophy. Analysis of the expression of marker genes of mitochondrial function, adipogenesis, inflammation and cell proliferation in ten 'buffalo hump' samples and ten subcutaneous fat samples from HIV-1-infected/HAART-treated patients, and in ten healthy controls. Quantitative real-time polymerase chain reaction analysis of mitochondrial DNA and gene transcripts, and immunoblot for specific proteins. 'Buffalo hump' patients had lower levels of mitochondrial DNA and mitochondrial DNA-encoded transcripts with respect to healthy controls. The uncoupling protein (UCP)-1 gene was expressed only in 'buffalo hump' fat. There were no significant changes in the expression of UCP2, UCP3 or of marker genes of adipogenesis in 'buffalo hump' patients relative to healthy controls. 'Buffalo hump' fat did not show the high expression of tumor necrosis factor-alpha and beta2-microglobulin identified in lipoatrophic subcutaneous fat from patients. The expression of the macrophage marker CD68 was also lower in 'buffalo hump' than in subcutaneous fat from patients. In contrast, 'buffalo hump' showed a higher expression of the cell proliferation marker PCNA. 'Buffalo hump' adipose tissue shows specific disturbances in gene expression with respect to subcutaneous fat from HIV-1-infected/HAART-treated patients. Mitochondrial alterations cannot explain the differential behavior of 'buffalo hump' with respect to adipose depots prone to lipoatrophy. The absence of a local inflammatory status in 'buffalo hump' may explain in part the differential behavior of this adipose tissue.
    AIDS (London, England) 04/2008; 22(5):575-84. · 4.91 Impact Factor

Publication Stats

110 Citations
74.71 Total Impact Points

Institutions

  • 2010–2013
    • University of Barcelona
      • • Instituto de Biomedicina (IBUB)
      • • Department of Biochemistry and Molecular Biology
      • • Departamento de Bioquímica y Biología Molecular
      Barcino, Catalonia, Spain
    • Hospital de la Santa Creu i Sant Pau
      Barcino, Catalonia, Spain
    • Molecular Biology Institute of Barcelona
      Barcino, Catalonia, Spain
  • 2008–2013
    • Instituto de Salud Carlos III
      Madrid, Madrid, Spain