The Relationship Between IFN-λ And The Rapid Virological Response To IFN-α In Chronic Hepatis C

Objective: The infection of hepatitis C virus can cause to acute orchronic inflammation of the liver. According to the world health organization,about180million people in the world are infected with HCV, and about42.5million of infected people in China. As a single strand RNA, HCV is dividedinto6genotypes. Genotype1and genotype4HCV are the difficult cure typesof hepatitis C virus. The genotype1HCV shows global distribution, aboutmore than70%of all HCV infection. Only20%-30%of acute HCV-infectedpeople can spontaneously clear the virus, but most of the HCV infected peoplego on to Chronic Hepatitis C. Then, the level of HCV-RNA start to stabilize,there is rare case of spontaneous recovery. About30percent of CHC patientswill develop to cirrhosis and hepatocelluar carcinoma. Even more, theincidence of hepatocellular carcinoma of them occur for20to30times to thenormal person. So the CHC has become a global public health issue, urgentneeding for the effective antiviral therapies.Interferon are important cytokinessecreted by the immune cells after a multifaceted virus infection, whichhaving the biological activities of antiviral, immune regulation and resistanceto cell proliferation. According to structural features and biological activities,IFN can be divided into three categories: type I, type II, and type III. I INFincluding IFN-α, IFN-β, IFN-ε, IFN-κ, IFN-δ, IFN-ζ, etc. IFN-α as antiviraldrugs is widely used in clinical application. The only one kind of ⅡINF isIFN-γ. Ⅲ INF including IFN-λ1(IL-29), IFN-λ2(IL-28A), and IFN-λ3(IL-28B).The current standard treatment of antiviral-HCV is the combination ofpolyethylene glycol interferon alpha (PEG-IFNα) and ribavirin (RBV). After4weeks of therapy, HCV-RNA is less than1000IU/mL called developed arapid virological response (RVR). If HCV-RNA after4weeks of antiviral treatment is still positive until in12weeks of therapy HCV-RNA less than1000IU/mL called developed a early virological response (EVR). Studieshave confirmed that RVR and EVR are good predictors of obtaining asustained virologic response (SVR), that is HCV-RNA is still less than1000IU/mL in24weeks after the end of the antiviral treatment. About88%-88%of those who got RVR would obtain the SVR. Once achieve SVR, more than99%can maintain virological for5years or longer. But not all the people canobtain the satisfactory sustained virological response. There are some factorsaffecting the rate of SVR including virus factors (such as HCV genotype, highbaseline levels HCV-RNA, etc.), drug factors (such as interferons alpha andRBV has obvious adverse reaction, interferons alpha pharmacokineticcharacteristics, etc.), host factors (such as the interferons alpha state of poortolerance and immune response, IFN-lambda3gene single nucleotidepolymorphism, etc.).In recent years, a series of analysis of Genome-wideAssociation Studies reported Single Nucleotide Polymorphism in the IL-28Bregion (e.g.rs12979860, rs8099917and rs12980275) as an associated factorwith the treatment response to interferon α of hepatitis C patients. Thosepatients carrying a protective genotypes of hepatitis C virus have moreprobability of obtaining SVR than those carrying not protective genotypesones.What’s more,they found that the levels of IL-29mRNA, IL-28A mRNA,IL-28B mRNA in peripheral blood mononuclear cells (PBMCs) of carryingprotective gene type patients are higher than those carrying not-protectivegene types. They also found that the levels of IL-29, IL-28A, IL-28B in theserum of carrying protective gene type patients are higher than those carryingnot-protective gene types. And compared with the healthy control group, thelevel of serum IL29in the patients with Chronic Hepatitis C is significantlyreduced, and the level of serum IL29of patients with Acute Hepatitis C isbetween them. The level of serum IL29in patients with spontaneous antivirusis significantly higher than those chronic hepatitis ones. In all, IL-28B SNPgene distribution can be used to predict clinical antiviral treatment curativeeffect, the patients of different antiviral treatment response have different levels of IFN-lambda. Thus we hypothesized that patients with differentlevels of IFN-ambda and the response to antiviral treatment may haverelevance. Studies have confirmed that although the receptors of IFN-lambdaand IFN-alpha and distribution are different, but they can through the samesignaling pathways-janus kinase signal transducer and activator of transcription-to conduction acting signals, induce expressionof a series of interferonIFN-stimulated genes, then play an antiviral, antitumor and immune regulat-ing biological activities. So IFN-lambda and interferons-alpha can play a roleof antiviral synergy in hepatitis c patients.There are many reports about IL-28B SNP genotype distribution can beused to predict the response to the antiviral treatment, but the study aboutdifferent levels of IFN-lambda in Hepatitis C patients and whether thedifferent levels have relevance with IFN-alpha’s antiviral response is still rare.Considering the RVR and EVR can predict the obtaining of SVR, and RVR isa better factor of predicting the SVR. Our study according to RVR divided thepatients into rapid virological response (RVR) group and the rapid virologicalresponse (N-RVR) group, aims to study IL-28B SNP gene distribution and thelevels of IFN-lambda1(IL-29), IFN-lambda2/3(IL-28A/B) in patients withdifferent outcomes of HCV infection and dif daferent responses to the antiviraltreatment of interferons alpha. Aim to know that if there is a correlationbetween IFN-lambda and the antiviral response to interferons alpha and itsclinical significance application.Methods: Select45patients with Chronic Hepatitis C, according to theresponse to interferon treatment conditions, they are divided into standardtreatment rapid virological response group (21cases) and standard treatmentno answer group (24cases).15healthy persons were enrolled in this study.1Biochemical indicator detection: application Olympus AU2700fullyautomatic biochemical analyzer (Japan) detect the ALT, AST levels ofserum, applied micro particle anti-HCV enzyme-linked immunoassaydetection, the fluorescence quantitative polymerase chain reaction methodto detect HCV-RNA level. 2The collected the peripheral blood mononuclear cells of anticoagulant freshblood were extracted the RNA. With RT-PCR and Western Blot assaysdetected the expression level relatively of IL-29, IL-28A and IL-28B inperipheral blood mononuclear cells.3Collect serum, then use the application of ELISA method to detect the levelof IL-29, IL-28A and IL-28B in serum.4Collect anticoagulant whole blood with peripheral (EDTA) of hepatitis Cpatients, then use the application of TapMan MGB probe method to detectthe genotype of IL-28B rs12979860.Results:1The results of IL-29, IL-28A and IL-28B level in rapid virological responsegroup’s serum is higher than the not rapid virological response group, thedifferences were statistically significant (P<0.01). The results of normalgroup is between them(Table1).2The results of IL-29, IL-28A and IL-28B mRNA in rapid virologicalresponse group’s PBMC is higher than not rapid virological response group,the differences were statistically significant (P<0.01). The results of normalgroup is between them(Table2).3The results of IL-29, IL-28A and IL-28B protein in rapid virologicalresponse group’s PBMC is higher than not rapid virological response group,the differences were statistically significant (P<0.01). The results of normalgroup is between them(Table3).4The levels of IL-29, IL-28A, IL-28B in serum and PBMC of the IL-28Brs12979860CC genotype carriers are obviously higher than those with CTand TT genotypes. The differences were statistically significant (P<0.05)（Table4,5,6).5Use SPSS13.0Pearson chi-square analysis to three genotypes of IL-28Brs12979860and RVR: the carriers of IL-28B rs12979860CC genotype gotsignificantly higher rate of RVR than the CT/TT genotype carriers. Thedifferences were statistically significant (P<0.05)(Table7).6A variety of factors with interferon alpha therapy rapid virological response (RVR) logistic regression analysis subjects to HCV-RNA baseline levelbefore treatment, HCV genotyping, IL-28B rs12979860genotype, and thelevel of interferon-lambda in serum and PBMC(Table8).Conclusions:1The high levels of IL-29, IL-28A and IL-28B in serum and PBMC areassociated with RVR.2The CC genotype carriers of IL-28B rs12979860have high RVR ratio.3The CC genotype of IL-28B rs12979860and high levels of IL-28B inPBMC associated with RVR.