Hepatitis C Virus and Interferon Type
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector REVIEW 10.1111/1469-0691.12797 Hepatitis C virus and interferon type III (interferon-k3/interleukin-28B and interferon-k4): genetic basis of susceptibility to infection and response to antiviral treatment E. Riva1, C. Scagnolari2, O. Turriziani2 and G. Antonelli2 1) Department of Integrated Research, Virology Section, University Campus Bio-Medico of Rome and 2) Department of Molecular Medicine, Virology Section, Sapienza University of Rome, Rome, Italy Abstract There has been a significant increase in our understanding of the host genetic determinants of susceptibility to viral infections in recent years. Recently, two single-nucleotide polymorphisms (SNPs), rs12979860 T/C and rs8099917 T/G, upstream of the interleukin (IL)-28B/interferon (IFN)-k3 gene have been clearly associated with spontaneous and treatment-induced viral clearance in hepatitis C virus (HCV) infection. Because of their power in predicting the response to IFN/ribavirin therapy, the above SNPs have been used as a diagnostic tool, even though their relevance in the management of HCV infection will be blunt in the era of IFN-free regimens. The recent discovery of a new genetic variant, ss469415590 TT/DG, upstream of the IL-28B gene, which generates the novel IFN-k4 protein, has opened up a new and alternative scenario to understand the functional architecture of type III IFN genomic regions and to improve our knowledge of the pathogenetic mechanism of HCV infection. A role of ss469415590 in predicting responsiveness to antiviral therapy has also been observed in HCV-infected patients receiving direct antiviral agents. The underlying biological mechanism that links the above IL-28B polymorphisms (in both IFN-k3 and IFN-k4)to spontaneous and treatment-induced clearance of HCV infection remains to be discovered. Despite this, shedding some light on this issue, which is the main aim of this review, may provide new insights into the general topic of ‘host genetics and viral infections’. Keywords: HCV infection, host genetics, interferon-k3, interferon-k4, single-nucleotide polymorphisms Article published online: 1 October 2014 Clin Microbiol Infect 2014; 20: 1237–1245 Corresponding author: E. Riva, Campus Bio-Medico University, via A del Portillo 200, 00128 Rome, Italy E-mail: [email protected] Introduction variants involved in treatment response in patients suffering from chronic viral infections. In recent years, there has been a significant improvement in Nevertheless, it should be mentioned that, due to the our understanding of the host genetic and genomic determi- rapid moving of the issue, it is quite difficult to obtain a full nants of susceptibility to viral infections, disease progression, picture of the field at present. This is why this review will and response to antiviral therapy. Indeed, common variants in focus only on the specific and limited issue of the some host loci that clearly influence viral disease progression association of common single-nucleotide polymorphisms have been documented at all levels, i.e. viral receptors, (SNPs) in the interferon (IFN)-k gene with disease outcome Toll-like receptors, DNA sensors, restriction factors, induc- and treatment response in chronic hepatitis C (CHC). We tion and production of cytokines, and/or the immune function believe that this is one of the best characterized examples of specific cellular effectors. A long list of host genes of the interplay between host genetics and chronic viral potentially affecting the natural course of viral diseases and infection that strongly suggests the consideration of individ- the effectiveness of antiviral therapy can therefore be ualization of antiviral therapy to effectively control viral provided. Table 1 shows the main consolidated host genetic infections. ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases 1238 Clinical Microbiology and Infection, Volume 20 Number 12, December 2014 CMI TABLE 1. Main host genomic determinants and therapy outcome Acronym Infection Effect References Interleukin-28B IL-28B HCV Spontaneous clearance and treatment response (SVR) 15–18 rs12979860 (T/C) and rs8099917 (T/G) Interferon-k4 IFN-k4 HCV Spontaneous clearance and treatment response (SVR) 13,64–66 ss469415590 or rs368234815 IFN-k4-TT/DG Inosine triphosphate tyrophosphatase ITPA HCV Ribavirin reduced anaemia induced by ITP deficiency 70 rs6051702 (A/C) rs1127354 (C/C, A/C, A/A), s7270101 (A/A, A/C, C/C) Vitamin D receptor VDR HCV Treatment response (SVR) 71 rs2228570 (T/C) Human leukocyte antigen C HLA-C HCV Treatment response 72 HLA-C (C1/C2) Killer immunoglobulin-like receptors KIR HCV Treatment response (SVR) 72 KIR2DL2 or 2DL3 KIR2DL3 in combination with HLAC2C2 Human leukocyte antigen A HLA HCV Treatment response (SVR) 73 HLA-DQB1*0301 and HLA-A*0201 in synergism with rs12979860 CC Low-density lipoprotein cholesterol LDLR HCV Treatment response (SVR) 74 receptor LDRL levels Human cytochrome P450 2B6 CYP2B6 HIV Efavirenz treatment decision and discontinuation 75 CYP2B6 516 (T/T) genotype is associated with higher efavirenz plasma exposure and increased CNS toxicity Human leukocyte antigen B HLAB*5701 HIV Abacavir treatment decision and discontinuation 76 Development of immune-mediated hypersensitivity reaction to abacavir Human leukocyte antigen A HLA-DRB*0101 HIV Nevirapine treatment decision and discontinuation 75 Nevirapine-associated hypersensitivity CNS, central nervous system; HCV, hepatitis C virus; ITP, inosine triphosphate; SVR, sustained virological response. IFN and Hepatitis C Virus (HCV) Infection ance of the virus from the blood) to be obtained in approximately 50% of the patients infected with HCV geno- type 1 (GT1 HCV), the most widely distributed and Infection by HCV, which was discovered only in 1989 with IFN-a-resistant genotype of HCV. Actually, several new drugs molecular techniques [1], represents a significant global health (with both host and virus targets), which are expected to cure issue, with an estimated prevalence of 130–200 million >90% of HCV infections, have reached or are going to reach infected individuals worldwide. So far, on the basis of their the market, probably making IFN-free regimens available in the genome sequences, six major genotypes (designated 1–6) and near future. several subtypes (named in alphabetical order from ‘a’) of HCV Since the beginning of IFN therapy, it was evident that a have been characterized. It is well known that the genotypes of proportion of patients did not respond to the therapy or HCV differ mainly in their response to antiviral therapy. relapsed after an initial response, and a significant variability in Acute HCV infections are usually asymptomatic and, even in response, even early after the first injection of IFN [2], could western countries, very rarely diagnosed. In some of the be demonstrated. This issue was addressed very intensely, and infected subjects, the infection is spontaneously eradicated, but soon many viral and host factors affecting the treatment the virus may persist in a high percentage (70–80%) of the response were identified (e.g. viral genotype, viral load level, infected individuals, leading to CHC. These subjects are at risk and wideness of viral quasi-species variability at the beginning (15–25%) of developing liver cirrhosis and hepatocarcinoma of therapy; acute vs. chronic infection; gender and age; level of after 10–40 years of infection, owing to the continuing fibrosis; body mass index and weight; insulin resistance; and necrosis and inflammation in the liver. presence of comorbidities). In the meantime, it was being Until recently, the standard antiviral therapy was based on recognized that the above factors could only partially explain IFN-a, a virus-induced cytokine that is rapidly produced in the the IFN response variability, and that, on the basis of the liver of HCV-infected subjects during the first 4–10 weeks of relevance of ethnicity to the outcome of the disease, the infection, and that is able to induce the expression of a number response to IFN may also have a genetic basis. Thus, of specific genes, collectively called IFN-stimulated genes (ISGs), researchers started to believe that there could be other coding for proteins with direct or indirect antiviral properties. important factors, mainly host genetic factors, that played a This therapy has undergone significant evolution and improve- pivotal role in the natural course of the disease, and that could ment over the years [from 1989 to 2012, when pegylated IFN also profoundly affect the response to antiviral therapy based (PEG) and the nucleoside analog ribavirin (RBV) were used], on a biological modifier, such as IFN. allowing a complete virological response (i.e. the disappear- ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20, 1237–1245 CMI Riva et al. Interferon Type III and HCV infection 1239 A number of studies were tentatively published on the issue gene resides on the short arm of chromosome 19 (19q13.13) [3–11], until genome-wide association studies (GWASs), which and encodes IFN-k3, which, together with IFN-k1 (IL-29), allowed study of the association between mapped SNPs and IFN-k2 (IL-28A) [12], and IFN-k4 [13], constitutes the IFN-k the presence of common conditions in large patient cohorts, family. Owing to their molecular structure, type III IFNs provided evidence that host genetic factors may profoundly belong to the IL-10 superfamily, but functionally they are affect the natural history of many diseases, including CHC and closely related to type I IFNs, which play a major role in its treatment. Specifically, these studies demonstrated a strong antiviral immunity [14]. Like type I IFNs, IFN-ks can be association between the presence of variants in the IFN-k3 triggered by viral infections and, through interaction with (also known as interleukin (IL)-28B) genetic region and the specific receptors distinct from those of type I IFNs, may PEG/RBV treatment response in CHC.