Outcome Of Hepatitis C Virus Infection Research Articles

Association of IFNL3 and IFNL4 polymorphisms with hepatitis C virus infection in a population from southeastern Brazil.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and associated complications such as liver cirrhosis and hepatocellular carcinoma (HCC). Viral and host factors are known to be predictors for antiviral therapy. Host factors that are predictors of sustained viral response (SVR) were discovered by genome-wide association studies (GWAS), including single-nucleotide polymorphisms (SNPs) in or near the interferon lambda gene (rs8099917, rs12979860 and rs368234815). The aim of the present study was to verify the genotype frequencies of SNPs rs8099917, rs12979860 and rs368234815 and to evaluate the association between SNPs and the outcome of HCV infection, taking into account the population ancestry. In this study, there was an association of the three polymorphisms with both clinical outcome and response to treatment with PEG-IFN and RBV. The polymorphisms rs12979860 and rs368234815 were associated with increased sensitivity (97.7%, 95% CI 87.2-100, and 93.3%, 95% CI 81.3-98.3; respectively) and with a greater predictive value of a positive response to treatment. In multivariable analysis adjusted by gender, age and ancestry, the haplotype G/T/ΔG was related to non-response to treatment (OR = 21.09, 95% CI 5.33-83.51; p < 0.001) and to a higher chance of developing chronic infection (OR = 5.46, 95% CI 2.06-14.46; p = 0.001) when compared to the haplotype T/C/TT. These findings may help to adjust our treatment policies for HCV infection based on greater certainty in studies with populations with such genetic characteristics, as well as allowing us to get to know the genetic profile of our population for these polymorphisms.

Hepatitis C virus/human T lymphotropic virus 1/2 co-infection: Regional burden and virological outcomes in people who inject drugs.

This review analyses current data concerning co-infection with hepatitis C virus (HCV) and human T lymphotropic virus (HTLV)-1/2 in people who inject drugs (PWID), with a particular focus on disease burden and global implications for virological outcome. In addition, the available treatment options for HTLV-1/2 are summarized and the ongoing and likely future research challenges are discussed. The data in this review was obtained from 34 articles on HCV/HTLV-1/2 co-infection in PWID retrieved from the PubMed literature database and published between 1997 and 2015. Despite unavailable estimates of the burden of HCV/HTLV-1/2 co-infection in general, the epidemiologic constellation of HTLV-1/2 shows high incidence in PWID with history of migration, incarceration, and other blood-borne infectious diseases such as HCV or human immunodeficiency virus. The most recent research data strongly suggest that HTLV-1 co-infection can influence HCV viral load, HCV sustained virological response to α-interferon treatment, and HCV-related liver disease progression. In short, outcome of HCV infection is worse in the context of HTLV-1 co-infection, yet more studies are needed to gain accurate estimations of the burden of HCV/HTLV-1/2 co-infections. Moreover, in the current era of new direct-acting antiviral treatments for HCV and proven HTLV-1/2 treatment options, prospective clinical and treatment studies should be carried out, with particular focus on the PWID patient population, with the aim of improving virological outcomes.

Bromodomain containing protein represses the Ras/Raf/MEK/ERK pathway to attenuate human hepatoma cell proliferation during HCV infection

Hepatitis C virus (HCV) infection facilitates the development of hepatocellular carcinoma (HCC). Activation of Ras/Raf/MEK/ERK pathway is found in more than 30% human cancers. Here, we revealed a novel mechanism underlying the regulation of hepatoma cell proliferation mediated by HCV. On one hand, hepatoma cell proliferation is facilitated by HCV infection through a positive feedback regulatory cycle. HCV promotes hepatoma cell proliferation by activating the Ras/Raf/MEK/ERK pathway, which in turn facilitates HCV replication to further enhance hepatoma cell proliferation. On the other hand, hepatoma cell proliferation is attenuated by the bromodomain containing 7 (BRD7), a tumor suppressor, through a negative feedback regulatory mechanism. After activation, the Ras/Raf/MEK/ERK pathway stimulates BRD7 production, which in turn represses the Ras/Raf/MEK/ERK pathway, leading to the attenuation of hepatoma cell proliferation. However, HCV persistent infection attenuates BRD7 gene expression and facilitates the protein degradation to release the Ras/Raf/MEK/ERK signaling, which results in the facilitation of hepatoma cell proliferation. Therefore, we proposed that the balance between BRD7 function and Ras/Raf/MEK/ERK activity is important for determining the outcomes of HCV infection and HCC development.

Glutathione S-Transferase M1 and T1 Gene Polymorphisms and the Outcome of Chronic Hepatitis C Virus Infection in Egyptian Patients.

We analysed the distribution of GSTM1 and GSTT1 gene polymorphisms in Egyptian patients with chronic hepatitis C, and investigated their relationship to the clinical outcome of chronic hepatitis C virus (HCV) infection. This study included 169 patients with chronic HCV infection and 145 healthy and matched controls.GSTM1 and GSTT1 polymorphisms were genotyped by multiplex polymerase chain reaction. Individual GSTM1 null and GSTT1 null genotypes were more frequent in patients versus control subjects [OR, 4 (95% CI, 2.5-6.4); P ˂ 0.001] and [OR, 1.7 (95% CI, 1.1-2.6); P = 0.025], respectively. The patient group showed a higher frequency of the combined GSTM1/GSTT1 double-null genotype than the control group [OR, 1.8 (95% CI, 1.1-2.9); P = 0.016]. The distribution frequencies of the combined GSTM1/GSTT1 double-null genotype were significantly different [OR, 0.5 (95% CI, 0.25-0.99); P = 0.049] between F0-F3 and F4. There were no significant differences between the two groups with regard to other genotypes. The combined GSTM1/GSTT1 double-null genotype was significantly increased in Child-Pugh C patients in comparison to Child-Pugh A+B (P = 0.02). There was no significant difference between different classes with regard to other genotypes. In conclusion, we identified an association between the combined GSTM1/GSTT1 double-null genotype and advanced liver fibrosis and outcome of chronic HCV infection in Egyptian patients.

Genetic variations in vitamin D receptor were associated with the outcomes of hepatitis C virus infection among Chinese population.

Vitamin D has been considered as an immune modulator, and exerted the effect through the vitamin D receptor (VDR). This study investigated the associations of single-nucleotide polymorphisms (SNPs) of VDR with the outcomes of Hepatitis C virus (HCV) infection. Three SNPs (rs2228570, rs757343 and rs739837) were genotyped by TaqMan assay among Chinese population, including 538 HCV spontaneous clearance subjects, 834 persistent infection subjects and 1030 uninfected subjects. Binary logistic analyses were used to control the effects of confounding factors. The results showed that subjects with the rs757343 A allele and rs739837 A allele had the significantly reduced risk of HCV susceptibility (all PBonferroni<0.05 in dominant/additive model). In the stratified analysis, the protection of rs757343 A allele and rs739837 A allele against HCV infection remained effective in some subgroups. In addition, patients carrying rs739837 CA genotype were less prone to develop persistent infection (PBonferroni=0.033) and such effect still work in several subgroups in the stratified analysis. Furthermore, haplotype analysis indicated that when compared with the most frequent GC haplotype, the haplotype carrying AA (odds ratio (OR)=0.66, 95% confidence interval (CI)=0.56-0.78) and GA (OR=0.64, 95% CI=0.47-0.85) suggested a protective effect. Our findings indicated that the polymorphisms of VDR are associated with the outcomes of HCV infection among Chinese population.

Interferon Response in Hepatitis C Virus (HCV) Infection: Lessons from Cell Culture Systems of HCV Infection.

Hepatitis C virus (HCV) is a positive-stranded RNA virus that infects approximately 130–170 million people worldwide. In 2005, the first HCV infection system in cell culture was established using clone JFH-1, which was isolated from a Japanese patient with fulminant HCV infection. JFH-1 replicates efficiently in hepatoma cells and infectious virion particles are released into the culture supernatant. The development of cell culture-derived HCV (HCVcc) systems has allowed us to understand how hosts respond to HCV infection and how HCV evades host responses. Although the mechanisms underlying the different outcomes of HCV infection are not fully understood, innate immune responses seem to have a critical impact on the outcome of HCV infection, as demonstrated by the prognostic value of IFN-λ gene polymorphisms among patients with chronic HCV infection. Herein, we review recent research on interferon response in HCV infection, particularly studies using HCVcc infection systems.

Natural evolution of hepatitis C virus infection in hemodialysis Tunisian patients and CTLA-4 SNP's.

To analyze the polymorphisms of CTLA-4 gene involved in the response against hepatitis C virus (HCV) infection. We recruited 500 hemodialysed patients from several hemodialysis centers, all HCV-antibody positive, spread over different regions of Tunisia, as part of a national survey in 2008 conducted in the laboratory of immunology at the Charles Nicolle hospital Tunisia, classified into two groups G1 (PCR+) and G2 (PCR-) according to the presence or absence of viral RNA. Of these patients, 307 were followed prospectively on a viral molecular level over a period from 2002 to 2008, divided into two groups based on the persistence and viral clearance. PCR-RFLP was performed for the analysis of SNPs (+49) A/G and (+6230) G/A CTLA-4 for these 500 patients and 358 healthy controls. Analysis of clinical and virological characteristics of our cohort suggests a nosocomial infection in our hemodialysed patients with transfusion history as a primary risk factor and a predominance of genotype 1b. The haplotype analysis revealed an increase of frequencies of GG (+49)/(CT60) CTLA-4 in the entire patients group compared to controls (P = 0.0036 and OR = 1.42; 95%CI: 1.12-1.79, respectively). This haplotype is therefore associated with susceptibility to HCV infection. Our study suggests a possible role of CTLA-4 polymorphisms in the outcome of HCV infection in the Tunisian hemodialysed population.

Natural Killer Cells in Viral Hepatitis.

Natural killer (NK) cells are traditionally regarded as first-line effectors of the innate immune response, but they also have a distinct role in chronic infection. Here, we review the role of NK cells against hepatitis C virus (HCV) and hepatitis B virus (HBV), two agents that cause acute and chronic hepatitis in humans. Interest in NK cells was initially sparked by genetic studies that demonstrated an association between NK cell–related genes and the outcome of HCV infection. Viral hepatitis also provides a model to study the NK cell response to both endogenous and exogenous type I interferon (IFN). Levels of IFN-stimulated genes increase in both acute and chronic HCV infection and pegylated IFNα has been the mainstay of HCV and HBV treatment for decades. In chronic viral hepatitis, NK cells display decreased production of antiviral cytokines. This phenotype is found in both HCV and HBV infection but is induced by different mechanisms. Potent antivirals now provide the opportunity to study the reversibility of the suppressed cytokine production of NK cells in comparison with the antigen-induced defect in IFNγ and tumor necrosis factor-α production of virus-specific T cells. This has implications for immune reconstitution in other conditions of chronic inflammation and immune exhaustion, such as human immunodeficiency virus infection and cancer.

The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways.

Diversity within the innate and adaptive immune response to hepatitis C is important in determining spontaneous resolution (SR) and treatment response. The aim of this study was to analyze how these variables interact in combination; furthering our understanding of the mechanisms that drive successful immunological clearance. Multivariate analysis was performed on retrospectively collected data for 357 patients previously genotyped for interferon (IFN)‐λ3/4, killer cell immunoglobulin (KIR), human leukocyte antigen (HLA) class I and II and tapasin. High resolution KIR genotyping was performed for individuals with chronic infection and haplotypes determined. Outcomes for SR, IFN response and cirrhosis were examined. Statistical analysis included univariate methods, χ2 test for trend, multivariate logistic regression, synergy and principal component analysis (PCA). Although KIR2DL3:HLA‐C1C1 (P = 0.027), IFN‐λ3/4 rs12979860 CC (P = 0.027), tapasin G in individuals with aspartate at residue 114 of HLA‐B (TapG:HLA‐B114D) (P = 0.007) and HLA‐DRB1*04:01 (P = 0.014) were associated with SR with a strong additive influence (χ2 test for trend P < 0.0001); favorable polymorphisms did not interact synergistically, nor did patients cluster by outcome. In the treatment cohort, IFN‐λ3/4 rs12979860 CC was protective in hepatitis C virus (HCV) G1 infection and KIR2DL3:HLA‐C1 in HCV G2/3. In common with SR, variables did not interact synergistically. Polymorphisms predictive of viral clearance did not predict disease progression. In summary, different individuals resolve HCV infection using discrete and non‐interacting immunological pathways. These pathways are influenced by viral genotype. This work provides novel insights into the complexity of the interaction between host and viral factors in determining the outcome of HCV infection.

Editorial: Recent Advances in HBV and HCV Immunology.

Viral hepatitis is a major public health problem. While a prophylactic vaccine is now available for hepatitis B virus (HBV), an estimated 240–350 million people worldwide are persistently infected with HBV (1–3). There is not yet an approved vaccine to prevent hepatitis C virus (HCV) infection, and between 130 and 200 million people are believed to be chronically infected worldwide (4–6). Untreated, HBV and HCV can each cause liver inflammation, fibrosis, and cirrhosis, and predispose patients to liver failure and hepatocellular carcinoma (2, 5). These infections are difficult and expensive to treat. Therapy for HBV infection may be lifelong, and a true cure with loss of HBV cccDNA from the liver is rarely achieved (2). IFNα-based therapy was the only option for chronic HCV infection until recently; these regimens were often poorly tolerated and frequently ineffective. An array of direct-acting antiviral drugs has greatly improved the outlook for HCV therapy since 2011 (7), but the expense of the new drugs may limit the number of people who benefit. We still do not understand the immunologic mechanisms leading to chronic HBV and HCV infection, how the immune system controls these viruses, and how the immune system contributes to disease pathogenesis. These topics must be understood in order to develop improved therapies and, at least in the case of HCV, an effective vaccine. Our goal in this Research Topic is to cover advancements toward this understanding. The immune response in the liver – where HBV and HCV each flourish – is incompletely understood. Many of our insights into the immune responses to HBV and HCV have come from studies of human peripheral blood, with limited comparisons to the cells in the liver. The liver is believed to constitute a tolerogenic environment as it receives portal venous blood rich in microbial products from the gut (8, 9). During persistent infection with either HCV or HBV, virus-specific T cells may decrease in number. The virus-specific T cells that can be found tend to have an exhausted phenotype including expression of inhibitory co-receptors, such as PD-1, CTLA-4, or Tim3 (10). Age at the time of exposure is an important predictor of the outcome of HBV infection: those infected in the perinatal period or early in childhood are likely to experience chronic infection, while those infected as adults often mount a successful immune response, with elimination of the template cccDNA from the liver (2). Antiviral immune responses wax and wane during chronic HBV infection. In this Topic, Schuch and colleagues review the roles of CD8+ T cells and natural killer cells in HBV infection (11). Sharma and colleagues present a study of Treg cells in HBV-associated hepatocellular carcinoma (12). Rajoriya and colleagues review the roles of γδ T cells in HBV or HCV infection as well as other conditions (13). HCV causes persistent infection in an estimated 50–85% of those exposed (14). Innate and adaptive immune responses can drive spontaneous clearance of HCV infection. In this Topic, Abdel-Hakeem and Shoukry review the role of the immune response in resolution of HCV infection (15). Sung and colleagues focus on the roles played by CD8+ T cells during acute HCV (16). Genome-wide association studies have highlighted a role for IFNλ in determining the outcome of HCV infection and IFNα-based antiviral therapy; this issue is reviewed by Laidlaw and Dustin (17). Cashman and colleagues discuss the roles of humoral immunity in acute and persistent HCV infection (18). Chronic HCV infection is also associated with extrahepatic disease; Sidharthan and colleagues present gene expression study showing a role for monocytes in HCV-associated mixed cryoglobulinemic vasculitis (19). Because of shared modes of transmission, up to 30% of individuals with HIV infection may also be infected with HCV; co-infected individuals have increased inflammation and accelerated liver damage (14). Cho and colleagues present a study of T cell phenotype, activation, and function in HCV–HIV co-infected patients, highlighting distinct changes in T cell function during co-infection – even when HIV is well controlled with highly active antiretroviral therapy (20).

Interleukin 28B.rs12979860 genotype does not affect hepatitis C viral load in Egyptians with genotype 4 chronic infection.

Several host and viral factors affect the natural history of Hepatitis C Virus (HCV) infection. Interleukin 28B (IL28B).rs12979860 single nucleotide polymorphism (SNP) was found to predict viral clearance with and without therapy. Subjects with the CC (favorable) genotype of IL28B.rs12979860 were more likely to spontaneously clear the infection and respond favorably to therapy. These data suggest that subjects with the "favorable" CC genotype might have a lower viral load when compared to those with the "unfavorable" TT genotype. Therefore, we examined the effect of IL28B.rs12979860 SNP on HCV viral load and clearance among HCV-infected Egyptians. This cross sectional study was conducted on 375 HCV antibody-positive subjects. Detection and quantification of HCV-RNA was determined by RT-PCR. IL28B.rs12979860 genotyping was performed using SYBR green real-time PCR and specific primers. Of 375 HCV-antibody positive subjects, 239 (63.7%) had chronic HCV infection while the remaining 136 (36.3%) subjects had spontaneously cleared the virus. The frequency of IL28-B CC, CT, and TT genotypes among spontaneous resolvers were 54.4%, 39.0%, and 6.6% while among the chronically infected subjects, they were 31.4%, 49.8%, and 18.8%, respectively. As expected, IL28 genotype predicted spontaneous HCV clearance (p < 0.001). The average HCV viral loads were 1.5 ± 0.69 x 10(6), 0.62 ± 0.11 x 10(6) and 0.51 ± 0.14 x 10(6) IU/ml among chronic subjects with the IL28B.rs12979860 CC, CT and TT genotypes, respectively (p > 0.05). In conclusion, our results show that IL28B.rs12979860 genotype does not affect viral load among chronic HCV infected Egyptians. These findings further confirm the complexity of viral host interactions in determining HCV infection outcome.

HCV F protein amplifies the predictions of IL-28B and CTLA-4 polymorphisms about the susceptibility and outcomes of HCV infection in Southeast China

Cytotoxic T lymphocyte associated antigen-4(CTLA-4) is an inhibitory receptor with great value in the progression of hepatitis C virus (HCV) infection related diseases. To determine the potential associations of IL-28B rs12979860 and CTLA-4 rs231775, rs3087243 and rs5742909 polymorphisms with the generation of HCV F protein, susceptibility and outcomes of HCV infection, a total of 375 healthy controls, 219 HCV spontaneous recovered patients and 600 chronic HCV patients from Southeast China were recruited and genotyped in this study. And the relative mRNA levels of CTLA-4 in T cells were detected. Logistic regression analysis showed that rs231775 A allele was associated with significantly higher rate of spontaneous viral clearance in anti-HCV F antibody negative patients (adjusted OR=0.512, P=0.008), but allele A was related to higher mRNA level of CTLA-4 with the generation of HCV F protein. And rs5742909 T allele added up to the risk of HCV infection chronicity significantly in patients with the presence of HCV F protein (adjusted OR=2.698, P=0.003). Also, the rs5742909 CC genotype, along with the presence of HCV F protein, indicated a significantly higher CTLA-4 level than that in anti-HCV F antibody negative patients. The AG+AA genotype of rs3087243 significantly increased the susceptibility to HCV infection in subjects over 56years old (adjusted OR=1.595, P=0.011). Genotype–genotype interaction between IL-28B rs12979860 and CTLA-4 rs3087243 was found to be significantly associated with increased susceptibility to HCV infection (adjusted OR=1.509, P=0.005). Haplotype analysis in CTLA-4 also showed significant association with the generation of HCV F protein. All these results indicated the importance of IL-28B and CTLA-4 polymorphisms and their associations with HCV F protein in the risk and chronicity of HCV infection in Chinese Han population in Southeast China.

Differential distribution of IL28B.rs12979860 single-nucleotide polymorphism among Egyptian healthcare workers with and without a hepatitis C virus-specific cellular immune response.

The CC genotype of the interleukin (IL)-28B.rs12979860 gene has been associated with spontaneous hepatitis C virus (HCV) clearance and treatment response. The distribution and correlation of an IL28B.rs12979860 single-nucleotide polymorphism (SNP) with HCV-specific cell-mediated immune (CMI) responses among Egyptian healthcare workers (HCWs) is not known. We determined this relationship in 402 HCWs who serve a patient cohort with ~85% HCV prevalence. We enrolled 402 HCWs in four groups: group 1 (n = 258), seronegative aviremic subjects; group 2 (n = 25), seronegative viremic subjects; group 3 (n = 41), subjects with spontaneously resolved HCV infection; and group 4 (n = 78), chronic HCV patients. All subjects were tested for an HCV-specific CMI response using an ex-vivo interferon-gamma (IFNγ) ELISpot assay with nine HCV genotype-4a overlapping 15-mer peptide pools corresponding to all of the HCV proteins. All subjects were tested for IL28B.rs12979860 SNP by real-time PCR. An HCV-specific CMI was demonstrated in ~27% of the seronegative aviremic HCWs (group 1), suggesting clearance of infection after low-level exposure to HCV. The frequency of IL28B.rs12979860 C allele homozygosity in the four groups was 49%, 48%, 49%, and 23%, while that of the T allele was 14%, 16%, 12 and 19%, respectively, suggesting differential distributions among subjects with different HCV status. As reported, IL28B.rs12979860 predicted the outcome of HCV infection (p < 0.05), but we did not find any relationship between the IL28B genotypes and the outcome of HCV-specific CMI responses in the four groups (p > 0.05). The data show differential IL28B.rs12979860 genotype distribution among Egyptian HCWs with different HCV status and could not predict the outcome of HCV-specific CMI responses.

Association of HLA class II alleles with hepatitis C virus clearance and persistence in thalassemia patients from Iran.

There is no published data on association of HLA class II alleles with clearance or persistence after acute hepatitis C virus (HCV) infection in patients from Iran. HLA DRB1, DQA1, and DQB1 alleles were determined using polymerase chain reaction amplification with sequence specific primers (PCR-SSP) on a total of 117 thalassemia patients (63 with chronic infection, and 54 with viral clearance) and 120 healthy controls. HLA-DRB1*0301 and DQA1*0501 alleles were found significantly present in patients with HCV clearance compared to those with chronic infection (P = 0.03 and P = 0.0007, respectively). By contrast, DRB1*0701, DQA1*0201, and DQB1*0602 alleles occurred significantly in those with chronic infection compared to those with viral clearance (P = 0.004, P = 0.007, and P = 0.02, respectively). As compared to the controls, DRB1*0301, DRB1*11, DQA1*0501, and DQB1*0301 alleles showed a significant decrease in chronic patients (P = 0.002, P = 0.001, P = 0.0001, and P = 0.0004, respectively). Furthermore, the haplotype frequencies of DRB1*0301, DQA1*0501, DQB1*0201, and DRB1*1101, DQA1*0501, DQB1*0301 were found significantly higher (P = 0.004 and P = 0.04, respectively) in patients with HCV clearance than those with chronic infection. By contrast, the haplotype DRB1*0701, DQA1*0201, DQB1*0201 occurred more frequently (P = 0.02) in those with chronic infection compared with those with viral clearance. These findings suggest that particular HLA alleles and related haplotypes may have an influence on the outcome of HCV infection among the Iranian patients. Some of the HLA alleles found in the Iranian patients are different from those reported elsewhere, suggesting that the immunogenetic makeup for HCV clearance or persistence may vary based on the ethnicity.

Post-transcriptional regulation of interferon lambda during viral infection (IRM5P.640)

Abstract Interferon lambda (IFN-λ) has gained increasing attention recently as an important mediator of antiviral protection in hepatitis C virus (HCV) infection. Similar to many cytokines, we have shown that expression of IFNL is regulated on a post-transcriptional level. Interestingly, single nucleotide polymorphisms (SNPs) within the IFNL genes dictate the outcome of acute HCV infection and serve as a prognostic marker for therapy of chronic HCV infection. Previously, we demonstrated that a functional SNP (rs4803217) within the 3'-untranslated region (UTR) of IFNL3 affects transcript stability and correlates with HCV clearance (G/G) or persistence (T/T) in infected patients and this is mediated by miRNAs and AU-rich elements. In our current study we have identified RNA-binding protein(s) (RBPs) that differentially regulate IFNL3 variants. We identified RBP candidates by carrying out mass spectrometry analysis on both variants of IFNL3 mRNA. We found that these candidates exclusively interact with the IFNL3 (T/T) mRNA. Intriguingly, gene expression of one candidate RBP is strongly induced upon stimulation of cells with HCV RNA or viral PAMP. Collectively, our data suggest that IFNL3 mRNA is post-transcriptionally regulated by miRNA and RBP-mediated mechanisms and that HCV potentially hijacks these regulatory mechanisms to suppress host antiviral responses.

Hepatitis C Virus Reinfection and Spontaneous Clearance of Reinfection—the InC3Study

We aimed to characterize the natural history of hepatitis C virus (HCV) reinfection and spontaneous clearance following reinfection (reclearance), including predictors of HCV reclearance. Data were synthesized from the 9 prospective cohorts of the International Collaboration of Incident Human Immunodeficiency Virus and HCV in Injecting Cohorts study, which evaluated HCV infection outcomes among people who inject drugs. Participants with primary HCV infection were classified as having achieved viral suppression if they had negative results of at least 1 subsequent HCV RNA test. Those with positive results of an HCV RNA test following viral suppression were investigated for reinfection. Viral sequence analysis was used to identify reinfection (defined as detection of heterologous virus with no subsequent detection of the original viral strain). Among 591 participants with acute primary HCV infection, 118 were investigated for reinfection. Twenty-eight participants were reinfected (12.3 cases/100 person-years; 95% confidence interval [CI], 8.5-17.8). Peak HCV RNA level was lower during reinfection than primary infection (P = .011). The proportion of individuals with reclearance 6 months after reinfection was 52% (95% CI, 33%-73%). After adjustment for study site, females with the IFNL4 (formerly IFNL3 and IL28B) rs12979860 CC genotype detected were more likely to have reclearance (hazard ratio, 4.16; 95% CI, 1.24-13.94; P = .021). Sex and IFNL4 genotype are associated with spontaneous clearance after reinfection.

Influence of IFNL3.rs12979860 and IFNL4.ss469415590 polymorphism on clearance of hepatitis C virus infection among Egyptians.

Single-nucleotide polymorphisms (SNPs) around the interferon lambda 3 (IFNL3; also known as interleukin 28B; IL28B) gene are associated with spontaneous hepatitis C virus (HCV) clearance. Interferon lambda 4 (IFNL4).ss469415590, in linkage disequilibrium (LD) with IFNL3.rs12979860 among the Caucasian population, has recently been identified as a potential functional variant. Our objective was to assess the LD between IFNL3.rs12979860 and IFNL4.ss469415590 and to compare their effect on the outcome of HCV infection among Egyptians, mainly infected with HCV genotype 4. One-hundred and eighty-five Egyptian HCV patients (77 spontaneous resolvers and 108 chronic subjects), and 122 healthy controls were genotyped for both IL28B.rs12979860 and IFNL4.ss469415590. Logistic regression models including factors with univariate association with the outcome of infection were calculated for each genetic marker. The LD was also calculated for the 122 healthy controls. The CC genotype of IFNL3.rs12979860 was more frequent among individuals with HCV spontaneous resolution than among those with chronic infection (57 vs. 27%; adjusted OR 3.84; 95% CI 2.02-7.30; p < 0.0001). Also, the TT/TT genotype of IFNL4.ss469415590 was more frequent among individuals with spontaneous resolution (49 vs. 20%; adjusted OR 4.17; 95% CI 2.12-8.19; p < 0.0001). Both markers were in LD (D' = 0.96; r (2) = 0.84). The IFNL3.rs12979860 and IFNL4.ss469415590 variants have comparable effects on spontaneous resolution of HCV among Egyptians, for whom both markers are closely linked.

TBX21 polymorphisms are associated with virus persistence in hepatitis C virus infection patients from a high-risk Chinese population

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and the varied outcomes of the infection depend on both viral and host factors. We have demonstrated that the HCV alternate reading frame protein (F protein) is related to Th1/Th2 bias which is involved in virus persistence in chronic hepatitis C (CHC) patients. The purpose of this study was to test the hypothesis that genetic variants of TBX21 (T cell specific T-box transcription factor) were associated with the outcomes of HCV infection and F protein generation. Three single nucleotide polymorphisms (SNPs) (rs17250932, rs2074190, rs4794067) in the TBX21 gene were genotyped in a case-control study in a cohort of a high-risk group, including 354 healthy controls and 747 CHC patients (190 anti-F protein antibody seronegative patients and 557 anti-F protein antibody seropositive patients). Results showed that the rs4794067 C allele in the TBX21 promoter was significantly more common in CHC patients (OR = 1.335, 95% CI = 1.058-1.684, P = 0.015), exceptionally in anti-F protein seropositive patients (OR = 1.547, 95% CI = 1.140-2.101, P = 0.005), compared with healthy controls. And the risk effect was also significantly high in patients with HCV 1b genotype and mild fibrosis (P = 0.021, P = 0.010, respectively). Compared with the most frequent haplotype TAT, haplotype analysis showed that the distribution of TAC was significantly different between the chronic HCV carrier group and the healthy group, and so was the anti-F antibody seronegativity group and the anti-F antibody seronegativity group (all P < 0.001). Our results suggested that TBX21 variants may be involved in the etiology of this disease.

Genetic variations of IL-28B and PD-1 are in association with the susceptibility and outcomes of HCV infection in Southeast China

Programmed cell death-1 (PD-1) is an important co-inhibitory molecule involved in the progression of chronic viral infections. To investigate the associations of three single nucleotide polymorphisms (SNPs) (rs10204525, rs2227982 and rs36084323) in PD-1 and a previously well-inquired SNP rs12979860 in IL-28B with the outcomes of hepatitis C virus (HCV) infection in Southeast China, a total of 375 healthy controls, 219 spontaneous resolved HCV patients and 600 chronic HCV patients were enrolled in this study. The generation of HCV F protein and PD-1 expression on T cells was determined. Multivariate logistic regression analysis showed no association of rs12979860 CC genotype with spontaneous clearance of HCV infection in our subjects. The generation of HCV F protein was significantly related to HCV infection chronicity, but no significant relationship was found between HCV F protein and SNPs in PD-1. The rs10204525 TT genotype was associated with an increased risk of HCV infection chronicity in age ⩽56years subgroup (adjusted OR=0.390, P=3.8×10−4). The C allele of rs10204525 played protective roles in females infected with HCV (adjusted OR=0.608, P=0.008). A significant higher percentage of PD-1 expression on T cells was observed in rs10204525 TT genotype when compared to CC genotype (P=0.047). Moreover, a significant genotype–genotype interaction between IL-28B rs12979860 CC and PD-1 rs10204525 TC+CC was found to be associated with higher rates of spontaneous clearance (adjusted OR=0.689, P=0.032). The combined effect of rs12979860 and rs10204525 was of great value in predicting the outcomes of HCV infection. These analyses showed the importance of IL-28B and PD-1 polymorphisms and their interactions in the outcomes of HCV infection in Chinese Han population in Southeast China.

Innate and adaptive genetic pathways in HCV infection.

Infection with hepatitis C virus (HCV) leads to a wide spectrum of clinical manifestations. This heterogeneity is underpinned by the host immune response and the genetic factors that govern it. Polymorphisms affecting both the innate and adaptive immunity determine the outcome of exposure. However the innate immune system appears to play a greater role in determining treatment-associated responses. Overall the effects of IFNL3/4 appear dominant over other polymorphic genes. Understanding how host genetics determines the disease phenotype has not been as intensively studied. This review summarizes our current understanding of innate and adaptive immunogenetic factors in the outcome of HCV infection. It focuses on how they relate to resolution and the progression of HCV-related liver disease, in the context of current and future treatment regimes.