Influence of Genetic Polymorphisms of Tumor Necrosis Factor Alpha and Interleukin 10 Genes on the Risk of Liver Cirrhosis in HIV-HCV Coinfected Patients.

<label>OBJECTIVE</label>Analysis of the contribution of genetic (single nucleotide polymorphisms (SNP) at position -238 and -308 of the tumor necrosis factor alpha (TNF-α) and -592 of the interleukin-10 (IL-10) promotor genes) and of classical factors (age, alcohol, immunodepression, antirretroviral therapy) on the risk of liver cirrhosis in human immunodeficiency (HIV)-hepatitis C (HCV) virus coinfected patients.<label>PATIENTS AND METHODS</label>Ninety one HIV-HCV coinfected patients (50 of them with chronic hepatitis and 41 with liver cirrhosis) and 55 healthy controls were studied. Demographic, risk factors for the HIV-HCV infection, HIV-related (CD4+ T cell count, antiretroviral therapy, HIV viral load) and HCV-related (serum ALT concentration, HCV viral load, HCV genotype) characteristics and polymorphisms at position -238 and -308 of the tumor necrosis factor alfa (TNF- α) and -592 of the interleukin-10 (IL-10) promotor genes were studied.<label>RESULTS</label>Evolution time of the infection was 21 years in both patients' groups (chronic hepatitis and liver cirrhosis). The group of patients with liver cirrhosis shows a lower CD4+ T cell count at the inclusion in the study (but not at diagnosis of HIV infection), a higher percentage of individuals with previous alcohol abuse, and a higher proportion of patients with the genotype GG at position -238 of the TNF-α promotor gene; polymorphism at -592 of the IL-10 promotor gene approaches to statistical significance. Serum concentrations of profibrogenic transforming growth factor beta1 were significantly higher in healthy controls with genotype GG at -238 TNF-α promotor gene. The linear regression analysis demonstrates that the genotype GG at -238 TNF-α promotor gene was the independent factor associated to liver cirrhosis.<label>CONCLUSION</label>It is stressed the importance of immunogenetic factors (TNF-α polymorphism at -238 position), above other factors previously accepted (age, gender, alcohol, immunodepression), on the evolution to liver cirrhosis among HIV-infected patients with established chronic HCV infections

Intracellular expression of tumor necrosis factor alpha, interleukin 6, transforming growth factor beta1 and interleukin 10 by monocytes from healthy individuals distributed in function of the -238 promotor gene polymorphism.

<p>Basal and LPS-stimulated concentration of tumor necrosis factor alpha, interleukin 6, transforming growth factor beta1 and interleukin 10 on supernatants of monocyte cultures. Abbreviations: TNF-α tumor necrosis factor alpha. IL-6, interleukin 6. TGF-β1, transforming growth factor beta 1. IL-10, interleukin 10. LPS, lipopolysaccharide.</p

Single nucleotide polymorphism of TNF-α and IL-10 genes studied in healthy controls and patients with HIV-HCV coinfection.

<p>Note: In Genotype frequency, “n” expresses the number of patients in which the analysis of each polymorphism was successful. By that, it could be no coincidence among the sum of genotype frequencies and the absolute number of patients.</p

Multivariant analysis of factors associated with the development of liver cirrhosis in HIV-HCV coinfected patients.

<p>Multivariant analysis of factors associated with the development of liver cirrhosis in HIV-HCV coinfected patients.</p

Immune activation response in chronic HIV-infected patients: influence of Hepatitis C virus coinfection.

We have analyzed the parameters (bacterial translocation, immune activation and regulation, presence of HCV coinfection) which could be implicated in an inappropriate immune response from individuals with chronic HIV infection. The influence of them on the evolution of CD4+ T cell count has been investigated.Seventy HIV-infected patients [monoinfected by HIV (n = 20), HCV-coinfected (with (n = 25) and without (n = 25) liver cirrhosis)] and 25 healthy controls were included. Median duration of HIV infection was 20 years. HIV- and HCV-related parameters, as well as markers relative to bacterial translocation, monocyte and lymphocyte activation and regulation were considered as independent variables. Dependent variables were the increase of CD4+ T cell count during the follow-up (12 months).Increased values of bacterial translocation, measured by lipopolysaccharide-binding protein, monocyte and lymphocyte activation markers and T regulatory lymphocytes were detected in HIV-monoinfected and HIV/HCV coinfected patients. Serum sCD14 and IL-6 were increased in HIV/HCV-coinfected patients with liver cirrhosis in comparison with those with chronic hepatitis or HIV-monoinfected individuals. Time with undetectable HIV load was not related with these parameters. The presence of cirrhosis was negatively associated with a CD4+ T cell count increase.In patients with a chronic HIV infection, a persistent increase of lipopolysaccharide-binding protein and monocyte and lymphocyte modifications are present. HCV-related cirrhosis is associated with more elevated serum concentrations of monocyte-derived markers. Cirrhosis influences the continued immune reconstitution of these patients

Serum concentrations of tumor necrosis factor-α (TNF-α) (white bars), interleukins 6 (IL-6) (lined bars) and 10 (IL-10) (dotted bars) and transforming growth factor beta 1 (TGF-β1) (black bars) in healthy controls (A) and in HIV-HCV coinfected patients with chronic hepatits (B) (n = 50) or liver cirrhosis (C) in function of the polymorphisms of -238 and -308 TNF-α and -592 IL-10 promotor genes.

<p>Serum concentrations of tumor necrosis factor-α (TNF-α) (white bars), interleukins 6 (IL-6) (lined bars) and 10 (IL-10) (dotted bars) and transforming growth factor beta 1 (TGF-β1) (black bars) in healthy controls (A) and in HIV-HCV coinfected patients with chronic hepatits (B) (n = 50) or liver cirrhosis (C) in function of the polymorphisms of -238 and -308 TNF-α and -592 IL-10 promotor genes.</p

Single nucleotide polymorphism of TNF-α and IL-10 genes studied in patients with HIV-HCV coinfection with chronic hepatitis or liver cirrhosis.

<p>Note: In Genotype frequency, “n” expresses the number of patients in which the analysis of each polymorphism was successful. By that, it could be no coincidence among the sum of genotype frequencies and the absolute number of patients.</p

Kaplan Meier curves of the development of liver cirrosis in HIV-HCV patients in function of the polymorphism at -238 position of the TNF-α promoter gene.

<p>Kaplan Meier curves of the development of liver cirrosis in HIV-HCV patients in function of the polymorphism at -238 position of the TNF-α promoter gene.</p

Markers of bacterial traslocation (A) (serum levels of lipopolysaccharide binding protein—LBP-, ng/ml); monocyte derived parameters [toll-like receptor 4 expression on monocyte (B) (CD14+TLR4+, percentage of blood CD14+ cells) and soluble CD14 receptor (C) (sCD14, ng/ml)], T CD4+-related populations [activated CD4+ T cells (D) (CD4+DR+, percentage of blood T CD4+ cells), naïve T CD4+ cells (E) (CD4+CD45RA+, percentage of blood T CD4+ cells), CD4+ T cells expressing the dead receptor PD1 (F) (CD4+PD1+, percentage of blood T CD4+ cells)], activated T CD8+ cells (G) (CD8+DR+, percentage of blood T CD8+ cells), and regulatory T cells [Treg, CD4+CD25highCD127lowFoxP3+ T cells (H) (percentage of blood T CD4+ cells) and serum concentration of transforming growth factor beta 1 (I) (TGF-β1, ng/ml)] in patients with HIV load undetectable for 12–36, 36–60 or > 60 months.

<p>Grey areas represent the normal values (range) of each parameter in healthy controls.</p

Lymphocyte and monocyte activation markers, T reg lymphocytes and bacterial translocation markers at inclusion in patients with an increase or decrease of CD4+ T cells/mm3 during the follow-up with reference to the median.

<p>Quantitative variables are expressed as median (interquartile range).</p><p>Lymphocyte and monocyte activation markers, T reg lymphocytes and bacterial translocation markers at inclusion in patients with an increase or decrease of CD4+ T cells/mm3 during the follow-up with reference to the median.</p