Glutaminolysis and lipoproteins are key factors in late immune recovery in successfully treated HIV-infected patients.

The immunological, biochemical and molecular mechanisms associated with poor immune recovery are far from known, and metabolomic profiling offers additional value to traditional soluble markers. Here, we present novel and relevant data that could contribute to better understanding of the molecular mechanisms preceding a discordant response and HIV progression under suppressive combined antiretroviral therapy (cART). Integrated data from nuclear magnetic resonance (NMR)-based lipoprotein profiles, mass spectrometry (MS)-based metabolomics and soluble plasma biomarkers help to build prognostic and immunological progression tools that enable the differentiation of HIV-infected subjects based on their immune recovery status after 96 weeks of suppressive cART. The metabolomic signature of ART-naïve HIV subjects with a subsequent late immune recovery is the expression of pro-inflammatory molecules and glutaminolysis, which is likely related to elevate T-cell turnover in these patients. The knowledge about how these metabolic pathways are interconnected and regulated provides new targets for future therapeutic interventions not only in HIV infection but also in other metabolic disorders such as human cancers where glutaminolysis is the alternative pathway for energy production in tumor cells to meet their requirement of rapid proliferation.

HIV-1/HAART-Related Lipodystrophy Syndrome (HALS) Is Associated with Decreased Circulating sTWEAK Levels.

BACKGROUND AND OBJECTIVES: Obesity and HIV-1/HAART-associated lipodystrophy syndrome (HALS) share clinical, pathological and mechanistic features. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine that plays an important role in obesity and related diseases. We sought to explore the relationship between HALS and circulating levels of soluble (s) TWEAK and its scavenger receptor sCD163. METHODS: This was a cross-sectional multicenter study of 120 HIV-1-infected patients treated with a stable HAART regimen; 56 with overt HALS and 64 without HALS. Epidemiological and clinical variables were determined. Serum levels of sTWEAK and sCD163 levels were measured by ELISA. Results were analyzed with Student's t-test, Mann-Whitney U and χ2 test. Pearson and Spearman correlation were used to estimate the strength of association between variables. RESULTS: Circulating sTWEAK was significantly decreased in HALS patients compared with non-HALS patients (2.81±0.2 vs. 2.94±0.28 pg/mL, p = 0.018). No changes were observed in sCD163 levels in the studied cohorts. On multivariate analysis, a lower log sTWEAK concentration was independently associated with the presence of HALS (OR 0.027, 95% CI 0.001-0.521, p = 0.027). CONCLUSIONS: HALS is associated with decreased sTWEAK levels.

Adipogenic/lipid, inflammatory, and mitochondrial parameters in subcutaneous adipose tissue of untreated HIV-1-infected long-term nonprogressors: significant alterations despite low viral burden.

BACKGROUND: 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. METHODS: 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), ß2-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). RESULTS: 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 ß2-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. CONCLUSIONS: 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.

Lipodystrophy and insulin resistance in combination antiretroviral treated HIV-1-infected patients: implication of resistin.

BACKGROUND: Little information is available with respect to the involvement of resistin in lipodystrophy and metabolic disturbances in HIV-1-infected patients treated with combination antiretroviral therapy (cART). We determined whether the resistin (rest) -420C>G single-nucleotide polymorphism and plasma resistin are associated with the development of lipodystrophy and metabolic disturbances in HIV-1-infected patients treated with cART. METHODS: The study group comprised 299 HIV-1-infected patients treated with a stable cART for at least 1 year (143 with lipodystrophy and 156 without) and 175 uninfected controls. Anthropometric, clinical, and metabolic variables were determined. Homeostasis model assessment for insulin resistance was used to evaluate insulin resistance. Plasma resistin levels were determined by enzyme-linked immunosorbent assay. The rest -420C>G was assessed using restriction fragment length polymorphism. Student t test, 1-way and 2-way analysis of variance, χ2 test, and Pearson and Spearman correlations were performed for statistical analysis. RESULTS: Genotypes containing the rest -420G variant allele were significantly more common in HIV-1-infected patients without lipodystrophy compared with those with lipodystrophy (P = 0.037). Infected patients had significantly greater plasma resistin levels than uninfected controls (P < 0.001). Among infected patients, plasma resistin levels were significantly lower in patients with lipodystrophy with respect to those without (P = 0.034). In infected patients, plasma resistin levels had a significant positive correlation with insulin and homeostasis model assessment for insulin resistance: P < 0.001 and P = 0.002 in the lipodystrophy subset and P = 0.002 and P = 0.03 in the nonlipodystrophy subset, respectively. CONCLUSIONS: In our cohort of white Spaniards, the rest -420C>G single-nucleotide polymorphism may be associated with cART-related lipodystrophy. Plasma resistin correlates with insulin resistance in infected patients with and without lipodystrophy.

No relationship between TNF-α genetic variants and combination antiretroviral therapy-related lipodystrophy syndrome in HIV type 1-infected patients: a case-control study and a meta-analysis.

Tumor necrosis factor alpha (TNF-α) is thought to be involved in the pathogenic and metabolic events associated with HIV-1 infection. We assessed whether carriage of the TNF-α gene promoter single nucleotide polymorphism (SNP) is associated with lipodystrophy and metabolic derangements in HIV-1-infected patients treated with cART. We also assessed variations in TNF-α receptor plasma levels. The study group comprised 286 HIV-1-infected patients (133 with and 153 without lipodystrophy) and 203 uninfected controls (UC). TNF-α -238G > A, -308G > A, and -863 C > A SNP were assessed using PCR-RFLPs on white cell DNA. Plasma sTNF-α R1 and R2 levels were measured by ELISA. Student's t test, the χ(2) test, Pearson correlations, and the logistic regression test were performed for statistical analysis. The TNF-α -308G > A SNP was significantly associated with lipodystrophy in the univariate analysis (p = 0.04). This association, however, was no longer significant in the multivariate analysis. A meta-analysis of the published literature and our own data, which included 284 patients with lipodystrophy and 338 without lipodystrophy, showed that there was no relationship between the TNF-α -238G > A and -308G > A SNP and lipodystrophy (p > 0.05 for all comparisons). HIV-1-infected patients had greater sTNF-α R2 plasma levels than UC (p = 0.001) whereas sTNF-α R1 and R2 levels were not significantly different in both the HIV-1-infected cohorts, lipodystrophy vs. nonlipodystrophy (p = NS). In our cohort of white Spaniards the TNF-α -238G > A, -308G > A, and -863C > A SNP were not associated with lipodystrophy in HIV-1-infected patients treated with cART. This finding was replicated in a meta-analysis of the published data, which showed no associations between the TNF-α -238G > A and -308G > A SNP and lipodystrophy. In HIV-1-infected patients under cART there is a systemic overproduction of sTNF-α R2, which is unrelated to the presence of lipodystrophy.

Effect of TNF-alpha genetic variants and CCR5 Delta 32 on the vulnerability to HIV-1 infection and disease progression in Caucasian Spaniards.

BACKGROUND: Tumor necrosis factor alpha (TNF-alpha) is thought to be involved in the various immunogenetic events that influence HIV-1 infection. METHODS: We aimed to determine whether carriage of the TNF-alpha-238G>A, -308G>A and -863 C>A gene promoter single nucleotide polymorphisms (SNP) and the CCR5 Delta 32 variant allele influence the risk of HIV-1 infection and disease progression in Caucasian Spaniards. The study group consisted of 423 individuals. Of these, 239 were uninfected (36 heavily exposed but uninfected [EU] and 203 healthy controls [HC]) and 184 were HIV-1-infected (109 typical progressors [TP] and 75 long-term nonprogressors [LTNP] of over 16 years' duration). TNF-alpha SNP and the CCR5 Delta 32 allele were assessed using PCR-RFLP and automatic sequencing analysis methods on white blood cell DNA. Genotype and allele frequencies were compared using the chi 2 test and the Fisher exact test. Haplotypes were compared by logistic regression analysis. RESULTS: The distribution of TNF-alpha-238G>A, -308G>A and -863 C>A genetic variants was non-significantly different in HIV-1-infected patients compared with uninfected individuals: -238G>A, p = 0.7 and p = 0.3; -308G>A, p = 0.05 and p = 0.07; -863 C>A, p = 0.7 and p = 0.4, for genotype and allele comparisons, respectively. Haplotype analyses, however, indicated that carriers of the haplotype H3 were significantly more common among uninfected subjects (p = 0.04). Among the infected patients, the distribution of the three TNF-alpha genetic variants assessed was non-significantly different between TP and LTNP: -238G>A, p = 0.35 and p = 0.7; -308G>A, p = 0.7 and p = 0.6: -863 C>A, p = 0.2 and p = 0.2, for genotype and allele comparisons, respectively. Haplotype analyses also indicated non-significant associations. Subanalyses in the LTNP subset indicated that the TNF-alpha-238A variant allele was significantly overrepresented in patients who spontaneously controlled plasma viremia compared with those who had a detectable plasma viral load (genotype comparisons, p = 0.02; allele comparisons, p = 0.03). The CCR5 Delta 32 distribution was non-significantly different in HIV-1-infected patients with respect to the uninfected population (p = 0.15 and p = 0.2 for genotype and allele comparisons, respectively) and in LTNP vs TP (p = 0.4 and p = 0.5 for genotype and allele comparisons, respectively). CONCLUSIONS: In our cohort of Caucasian Spaniards, TNF-alpha genetic variants could be involved in the vulnerability to HIV-1 infection. TNF-alpha genetic variants were unrelated to disease progression in infected subjects. The -238G>A SNP may modulate the control of viremia in LTNP. Carriage of the CCR5 Delta 32 variant allele had no effect on the risk of infection and disease progression.

Pharmacogenetics of adverse effects due to antiretroviral drugs.

The availability of highly active antiretroviral therapy has markedly improved the survival rate and quality of life in patients infected with HIV. At present, however, there is still no cure for HIV and those undergoing treatment have to do so for life. The use of antiretroviral drugs has been associated with several toxicities that limit their success. Some acute and chronic toxicities associated with these drugs include hypersensitivity reactions, neurotoxicity, nephropathy, liver damage, and the appearance of body fat redistribution syndrome and the different metabolic alterations that accompany it. Some of these toxicities are family- or even drug-specific. Since not all patients that take a particular antiretroviral medication develop the adverse effect that has been attributed to that drug, it has therefore been postulated that there must be a genetically conditioned individual predisposition to developing the adverse effect. Pharmacogenetics is the science that studies interindividual variations in the response to and toxicity of pharmaceuticals due to variations in the genetic composition of individuals - in other words, how a person's genetic make-up influences the favorable or adverse effects of a certain treatment. Sufficient advances have been made in this discipline to allow this fertile field of research to move out of the basic science laboratory and into clinical applications. The present article reviews the investigations that have been published regarding the association between genetic determinants of persons infected with HIV and clinical toxicity resulting from different antiretroviral drugs. Special emphasis is devoted to the studies that have resulted in clinical applications such as that of the pre-screening of HLA B*5701 for avoiding abacavir-related hypersensitivity syndrome.

The IL-6 system in HIV-1-infection and in HAART-related fat redistribution syndromes.

We determined the IL-6 -174 G>C single nucleotide polymorphism, IL-6 mRNA expression in subcutaneous adipose tissue (SAT) and IL-6 plasma levels in HIV-1-infected patients with and without lipodystrophy and uninfected controls. HIV-1-infected patients had a greater prevalence of the IL-6 -174 C/C genotype and the C allele, higher SAT IL-6 mRNA expression and plasma IL-6 levels than controls. The IL-6 -174 G>C genotype distribution and allele frequencies, SAT IL-6 mRNA expression and IL-6 plasma levels were non-significantly different between HIV-1-infected patients with and without lipodystrophy.