ABSTRACT
BACKGROUND: The underlying mechanisms of incomplete immune reconstitution in treated HIV-positive patients are very complex and may be multifactorial, but perturbation of chemokine secretion could play a key role in CD4+T-cell turnover. METHODS: We evaluated the circulating baseline and 48-week follow-up concentrations of SDF-1/CXCL12, fractalkine/CX3CL1, MCP-1/CCL2, MIP-α/CCL3, MIP-ß/CCL4 and RANTES/CCL5, and we estimated their association with CXCL12, CX3CR1, CCR2, CCL5 and CCR5 single nucleotide polymorphisms (SNPs) to investigate multiple chemokine-chemokine receptor signatures associated with immune dysregulation preceding poor immune recovery. FINDINGS: The circulating concentrations and gene expression patterns of SDF-1/CXCL12 (CXCL12 rs1801157) and MCP-1/CCL2 (CCR2 rs1799864_814) were associated with immune recovery status. CCR2 rs1799864_814 and CCR5 rs333_814 (Δ32) determine the baseline plasma RANTES and MIP-α concentrations, respectively, in participants with poor immune response. INTERPRETATION: SDF-1/CXCL12 and MCP-1/CCL2 could be considered prognostic markers of immune failure despite suppressive antiretroviral therapy. The strong linkage disequilibrium (LD) between CCR2 rs1799864_814 and CCR5 rs1800024 indicated that the alleles of each gene are inherited together more often than would be expected by chance. FUNDING: This work was supported by Fondo de Investigacion Sanitaria and SPANISH AIDS Research Network (ISCIII-FEDER); AGAUR and Gilead Fellowship. FV and YMP are supported by grants from the Programa de Intensificación (ISCIII) and Servicio Andaluz de Salud, respectively. JVG,EY and LR are supported by the Instituto de Salud Carlos III (ISCIII). AR is supported by Departament de Salut, Generalitat de Catalunya and by the Instituto de Salud Carlos III (ISCIII).
Subject(s)
Chemokine CCL2/blood , Chemokine CCL2/genetics , Chemokine CXCL12/blood , Chemokine CXCL12/genetics , Genetic Variation , Receptors, CCR5/genetics , Adult , Alleles , Antiretroviral Therapy, Highly Active , CD4 Lymphocyte Count , Case-Control Studies , Female , Genetic Association Studies , Genotype , HIV Infections/blood , HIV Infections/drug therapy , HIV Infections/genetics , HIV Infections/immunology , Humans , Immunity , Immunomodulation/genetics , Male , Middle Aged , Prognosis , Risk FactorsABSTRACT
A relationship between polymorphisms in genes encoding interleukin 7 (IL-7) and its cellular receptor (IL-7R) and antiretroviral therapy (ART)-associated immune recovery in HIV subjects has been previously reported. However, details of this relationship remain unclear, and the association of these polymorphisms with circulating IL-7/IL-7R levels is scarce. Here, we explored whether IL-7/IL-7R axis was associated with quantitative CD4+ T-cell recovery in HIV-infected subjects. IL-7/IL-7R polymorphisms were assessed by genotyping, and multiple inheritance models were used to estimate both, their association with low pre-ART CD4+ T-cell counts and incomplete immune recovery status after 48 weeks of suppressive ART. Integrated data from genetic variants association and soluble plasma IL-7/IL-7R quantification suggest that IL-7/IL-7R genotype expression could alter the homeostatic balance between soluble and membrane-bound receptors. The haplotype analyses indicates that allele combinations impacts pre-ART circulating CD4+ T-cell counts, immune recovery status and the absolute increment of CD4+ T-cell counts. The knowledge about how IL-7/IL-7R axis is related to quantitative CD4+ T-cell recovery and immune recovery status after initiating ART could be useful regarding T-cell reservoirs investigations in HIV subjects.
Subject(s)
Anti-HIV Agents/therapeutic use , HIV Infections/immunology , Interleukin-7/genetics , Receptors, Interleukin-7/genetics , Adult , CD4 Lymphocyte Count , Cohort Studies , Female , HIV Infections/drug therapy , Homeostasis , Humans , Interleukin-7/blood , Male , Middle Aged , Receptors, Interleukin-7/bloodABSTRACT
OBJECTIVE: The aim of this study was to analyse the expression of crucial genes in fatty acid metabolism in visceral (VAT) and subcutaneous (SAT) adipose tissue samples from morbidly obese women. METHODS: The VAT and SAT expression of key genes in 145 morbidly obese women (MO, BMI > 40 Kg/m(2) ) and 18 normal weight control women by RT-PCR and Western Blot was analyzed. RESULTS: In SAT, the expression levels of the genes related to lipogenesis and fatty acid oxidation were significantly lower in MO than in controls. In VAT, most of the lipogenic genes studied had similar expression levels in MO and control cohort. Regarding inflammation, IL6 was significantly higher in MO in both tissues whereas TNFα mRNA expression was significantly higher only in VAT. CONCLUSIONS: Our results indicate that in morbidly obese patients, lipogenesis and fatty acid oxidation are downregulated in SAT, whereas in VAT these pathways are almost unchanged. By contrast, inflammation is induced in both adipose tissues. It is hypothesized that, in this type of extreme obesity, SAT works to limit any further development of fat mass, decreasing the expression of lipogenic and FA oxidative genes whereas VAT depot might have lost this capability.
