Induction of IgA and sustained deficiency of cell proliferative response in chronic hepatitis C

AIM： In the present study, antibody and peripheral blood mononuclear cells （PBMC） proliferative responses against hepatitis C virus （HCV） antigens were evaluated in HCV chronically infected patients. METHODS： Paired serum and PBMC samples were taken six months apart from 34 individuals, either treated or not, and tested by enzyme-linked immunosorbent assay （ELISA） and carboxyfluorescein succinimidyl ester staining. RSULTS： Over 70% of the patients showed specific IgG and IgM against capsid, E1 and NS3, while HVR-1 was recognized by half of the patients. An increase in the levels of the anti-capsid IgM （P = 0.027） and IgG （P = 0.0006） was observed in six-month samples, compared to baseline. Similarly, a significantly higher percent of patients had detectable IgA reactivity to capsid （P = 0.017） and NS3 （P = 0.005） after six months, compared to baseline. Particularly, IgA against structural antigens positively correlated with hepatic damage （P = 0.036）. IgG subclasses evaluation against capsid and NS3 revealed a positive recognition mediated by IgG1 in more than 80% of the individuals. On the contrary, less than 30% of the patients showed a positive proliferative response either of CD4＋ or CD8＋ T cells, being the capsid poorly recognized. CONCLUSION： These results confirm that while the cellular immune response is narrow and weak, a broad and vigorous humoral response occurs in HCV chronic infection. The observed correlation between IgA and hepatic damage may have diagnostic significance, although it warrants further confirmation.     

Neutralizing antibodies and broad,functional T cell immune response following immunization with hepatitis C virus proteins-based vaccine formulation

HCV is a worldwide health problem despite the recent advances in the development of more effective therapies. No preventive vaccine is available against this pathogen. However, non-sterilizing immunity has been demonstrated and supports the potential success of HCV vaccines. Induction of cross-neutralizing antibodies and T cell responses targeting several conserved epitopes, have been related to hepatitis C virus (HCV) clearance. Therefore, in this work, the immunogenicity of a preparation (MixprotHC) based on protein variants of HCV Core, E1, E2 and NS3 was evaluated in mice and monkeys. IgG from MixprotHC immunized mice and monkeys neutralized the infectivity of heterologous HCVcc. Moreover, strong CD4+ and CD8+ T cells proliferative and IFN-γ secretion responses were elicited against HCV proteins. Remarkably, immunization with MixprotHC induced control of viremia in a surrogate challenge model in mice. These results suggest that MixprotHC might constitute an effective immunogen against HCV in humans with potential for reducing the likelihood of immune escape and viral persistence.     

HCV-specific immune responses induced by CIGB-230 in combination with IFN-α plus ribavirin

AIM:To analyze hepatitis C virus(HCV)-specific immune responses in chronically infected patients under triple therapy with interferon-α(IFN-α)plus ribavirin and CIGB-230.METHODS:CIGB-230 was administered in different schedules with respect to IFN-αplus ribavirin therapy.Paired serum and peripheral blood mononuclear cells(PBMC)samples from baseline and end of treatment were analyzed.The HCV-specific humoral response was tested by enzyme-linked immunosorbent assay,neutralizing antibodies were evaluated by cell culture HCV neutralization assays,PBMC proliferation was assayed by carboxyfluorescein succinimidyl ester staining and IFN-γsecretion was assessed by enzyme-linked immunospot.Data on virological and histological response and their association with immune variables are also provided.RESULTS:From week 12 to week 48,all groups of patients showed a significant reduction in mean leukocyte counts.Statistically significant reductions in antibody titers were frequent,but only individuals immunized with CIGB-230 as early add-on treatment sustained the core-IgG response,and the neutralizing antibody response was enhanced only in patients receiving CIGB-230.Cell-mediated immune responses also tended to decline,but significant reductions in IFN-γsecretion and total absence of core-specific lymphoproliferation were exclusive of the control group.Only CIGB-230-immunized individuals showed de novo induced lymphoproliferative responses against the structural antigens.Importantly,it was demonstrated that thequality of the CIGB-230-induced immune response depended on the number of doses and timing of administration in relation to the antiviral therapy.Specifically,the administration of 6 doses of CIGB-230 as late addon to therapy increased the neutralizing antibody activity and the de novo core-specific IFN-γsecretion,both of which were associated with the sustained virological response.CONCLUSION:CIGB-230,combined with IFN-α-based therapy,modifies the immune response in chronic patients.The study provides evidence for the design of more effective therapeutic vaccine interventions against HCV.     

Gender‐Specific Association Between ABCC2 ‐24C>T SNP and Reduction in Triglycerides in Chilean Patients Treated With Atorvastatin

Statins are the first‐line therapy prescribed to lower plasma cholesterol levels. Although being safe and showing several beneficial cholesterol‐independent pleiotropic effects, a significant variability regarding statin's therapeutic goals has been abundantly documented, but less understood. We aimed to investigate the influence of the ABCC2 ‐24C>T single nucleotide polymorphism on Chilean hypercholesterolaemic individuals treated for 4 weeks with 10 mg/day atorvastatin. A total of 127 individuals medicated with atorvastatin 10 mg/day/4 weeks were included. Lipid profiles were determined before and after drug administration by conventional assays. Genotyping of the ABCC2 rs717620 SNP (‐24C>T) was performed with TaqMan^® Drug Metabolism Genotyping Assays. As expected, atorvastatin reduced TC, LDL‐C and TG concentrations (p < 0.05). Also, HDL‐C levels were increased (p < 0.05). Minor allele frequency for the rs717620 was 0.232. Overall, atorvastatin response was not associated with the ABCC2 rs717620 SNP (p > 0.05). Nonetheless, in male individuals carrying the ‐24T allele, we observed an attenuated reduction in both TG values and the TG/HDL‐C ratio after 10 mg/day atorvastatin. This study indicates that TG levels and the TG/HDL‐C ratio are affected by the rs717620 SNP in Chilean males but not female individuals after atorvastatin treatment.