INFLUENZA DEI POLIMORFISMI DI IL-28B E SLC29A1 SULLA RISPOSTA ALLA TERAPIA CON INTERFERONE PEGILATO E RIBAVIRINA IN PAZIENTI COINFETTI HIV-HCV

HCV coinfection is the major health complication for HIV patients. More frequently than some years ago their death is related to HCV induced end-stage liver disease rather than AIDS induced by HIV. The reason for this is the significant progress in development of antiretroviral therapy allowing HIV infected patients the lifespan close to the range of uninfected people, on the other hand higher than in HCV monoinfected patients susceptibility to develop liver diseas and low adherence to the anti-HCV therapy regimen resulting that only about 60% of them can be cured. Additionally, it is now well established that in patients monoinfected with HCV as well as those who are coinfected with HIV, spontaneous or therapy induced clearance of the HCV is associated with single nucleotide polymorphism near or in the IL-28b gene. IL-28b gene SNPs together with HCV genotype, viral load, ethnicity, and age are among independent pretreatment predictors of SVR among HCV monoinfected patients, whereas during treatment the best predictor of SVR is viral dicline at 4th week after therapy initiation. The mechanism through which SNP’s near/in the IL-28b gene can affect the spontaneous or therapy induced clearance of the virus are not know. Some studies show the genotype dependent mRNA expression of IL-28b in peripheral blood mononuclear cells of healthy and HCV infected patients. In our study we have first determined the distribution of genotypes for 5 different SNP’s of which 4 are located in intronic part near IL-28a/b genes and include: rs12979860, rs809917, rs12980275, rs11881222 and 1 is located in equilibrative nucleoside transporter 1 (ENT1) gene which is involved in cellular uptake of ribavirin. The distribution of genotypes of these SNP’s could let us understand the reasons for which some patients do not clear or respond to the anti-HCV therapy but also to understand the kinetics of suppression or not of viral load. Through analyses of IL-28a and IL-28b gene expression in PBMC of studied groups we have also attempted to understand if the tested SNP’s arround the IL-28a/b genes can determine the expression of these cytokines and thus the predispositions of some people to better clear the HCV virus. What we have optained can be summarized in the following steps: In group of Italian population of HCV/HIV coinfected patients we found significant association between genetic polymorphisms near IL-28a/b genes and HCV clearance. We determined the allels of studied SNP’s that predispose the host to clear the virus; In group of patients who needed the support the anti-HCV therapy we found that the same genetic SNP’s as for patients who cleared the virus determine the sustained virological response. Additionaly in achiving this status were important the HCV genotype, HCV load, and cART. We found also genetic association between HCV load detection at 3rd month after application of therapy and SNP in ENT1 gene implying possible effect of use of ribavirin in the therapy. IL-28a and IL-28b gene expression analyses showed that IL-28a is in general expressed at higher level than in IL-28b in any of tested groups. However, in contrast to IL-28a, IL-28b is downregulated in patients who do not respond to the therapy in comparison to those with SVR. Moreover, expression of IL-28b is higher among those HCV patients who carry preferential for HCV spontaneous clearance and therapy response alleles of tested SNP’s near IL28a/b genes. This observation is not evident among healthy patients suggesting that different levels of expression of IL-28b between subgroups of HCV patients are the result of secondary causes.