The relationship between IFNL4 genotype and the rate of fibrosis in hepatitis C patients.

Introduction: IFNL4 rs12979860 genotype CC is associated with increased ALT activity and liver stiffness in hepatitis C virus (HCV) genotype (G) 3 infection but not in G1. The primary aim of this study is to assess an interaction between IFNL4 genotype, viral genotype and the stage of liver fibrosis. Secondary aims are to study the potential interactions between IFNL4 genotype, viral genotype and viral load as well as ALT levels. Methods: We performed a cross sectional study of patients with untreated chronic hepatitis C. Inflammation and liver fibrosis were scored using METAVIR. DNA was extracted from serum samples and the rs12979860 was genotyped using a custom made Taqman assay. Results: About 304 consecutive patients with chronic Hepatitis C were included. 52% had G1 infection and 48% had G3. Among patients with G3, advanced fibrosis or cirrhosis (F3F4) was present in 35% of the patients with IFNL4 CC and 28% with CT/TT (p = 0.24). Among patients with G1, F3F4 was present in 20% of the patients with IFNL4 CC and 19% with CT/TT (p = 0.52). IFNL4 CC was associated with higher mean value of normalized (n)ALT both in HCV G1 and G3 infection. Conclusions: IFNL4 genotype was not a predictor of advanced liver fibrosis in G3 or G1 infected patients. IFNL4 CC predicted a higher mean value of ALT among both G1 and G3 infected patients.

Factors associated with hepatitis C virus RNA levels in early chronic infection: the InC3 study.

Improved understanding of natural history of hepatitis C virus (HCV) RNA levels in chronic infection provides enhanced insights into immunopathogenesis of HCV and has implications for the clinical management of chronic HCV infection. This study assessed factors associated with HCV RNA levels during early chronic infection in a population with well-defined early chronic HCV infection. Data were from an international collaboration of nine prospective cohorts studying acute HCV infection (InC(3) study). Individuals with persistent HCV and detectable HCV RNA during early chronic infection (one year [±4 months] postinfection) were included. Distribution of HCV RNA levels during early chronic infection was compared by selected host and virological factors. A total of 308 individuals were included. Median HCV RNA levels were significantly higher among males (vs females; 5.15 vs 4.74 log IU/mL; P < 0.01) and among individuals with HIV co-infection (vs no HIV; 5.89 vs 4.86; P = 0.02). In adjusted logistic regression, male sex (vs female, adjusted odds ratio [AOR]: 1.93; 95%CI: 1.01, 3.69), interferon lambda 4 (IFNL4) rs12979860 CC genotype (vs TT/CT; AOR: 2.48; 95%CI: 1.42, 4.35), HIV co-infection (vs no HIV; AOR: 3.27; 95%CI: 1.35, 7.93) and HCV genotype G2 (vs G3; AOR: 5.40; 95%CI: 1.63, 17.84) were independently associated with high HCV RNA levels (>5.6 log IU/mL = 400 000 IU/mL). In conclusion, this study demonstrated that IFNL4 rs12979860 CC genotype, male sex, HIV co-infection and HCV genotype G2 are associated with high HCV RNA levels in early chronic infection. These factors exert their role as early as one year following infection.

The Interferon-Lambda Family Celebrates 20 Years of Scientific Discovery.

It has now been 20 years since the original discovery of the interferon λ (IFN-λ) family (Kotenko et al., 2003; Sheppard et al., 2003) and 10 years since the subsequent discovery of IFN-λ4 (Prokunina-Olsson et al., 2013). The IFN-λ family (type III IFNs) includes 4 members: IFN-λ1, 2, 3, and 4, and all 4 of these proteins signal through the same heterodimeric receptor complex: IFN-λR1 plus IL-10R2. Throughout the past 20 years, much has been learned about the IFN-λ family and the important role of these cytokines in antiviral responses against viruses such as hepatitis C virus, influenza A virus, and SARS-CoV-2. This special issue of the Journal of Interferon & Cytokine Research (JICR) features a group of new reports that highlight recent developments regarding various aspects of IFN-λ-mediated responses. Many of these reports were first presented during the Interferon Lambda 2022 Satellite Meeting after the "Cytokines 2022" meeting in Hawaii. These articles underscore the fact that our understanding of the IFN-λ family continues to evolve and remains a critical subject area for additional future research.

IFNL4 Genotype Does Not Associate with CD4 T-Cell Recovery in People Living with Human Immunodeficiency Virus.

Immune non-responders (INRs) are people with HIV infection who fail to restore their CD4 T-cell counts in spite of prolonged virologic suppression, a condition associated with higher rates of all-cause mortality. The mechanisms of immune non-response are not entirely clear. We used existing clinical and genetic data from AIDS Clinical Trials Group clinical trials to ask whether an IFNL4 single-nucleotide polymorphism, shown to be associated with outcomes for other infectious diseases, correlated with immune non-response for HIV. Analysis of data from 426 participants with clearly defined CD4 T-cell recovery phenotypes, including 88 INRs with CD4 < 200 cells/mm3 after 2 years of suppressive antiretroviral therapy, did not identify an association of IFNL4 genotype with immune non-response. Thus, the IFNL4 genotype is unlikely to influence immunologic recovery.