TY - JOUR AU - Silva, Andréa Marques Vieira da AU - Alvarado-Arnez, Lucia Elena AU - Azamor, Tamiris AU - Batista-Silva, Leonardo Ribeiro AU - Leal-Calvo, Thyago AU - Bezerra, Ohanna Cavalcanti de Lima AU - Ribeiro-Alves, Marcelo AU - Kehdy, Fernanda de Souza Gomes AU - Neves, Patrícia Cristina da Costa AU - Bayma, Camilla AU - Silva, Jane da AU - Souza, Alessandro Fonseca de AU - Muller, Marcelo AU - Andrade, Elisabete Ferreira de AU - Andrade, Ana Carolina Magalhães AU - Santos, Eliane Matos dos AU - Xavier, Janaína Reis AU - Maia, Maria De Lourdes De Sousa AU - Meireles, Rolando Páez AU - Cuni, Hugo Nodarse AU - Sander, Guilherme Becker AU - Picon, Paulo Dornelles AU - Matos, Denise C S AU - Moraes, Milton Ozório PY - 2021 M3 - Original Research TI - Interferon-lambda 3 and 4 Polymorphisms Increase Sustained Virological Responses and Regulate Innate Immunity in Antiviral Therapy With Pegylated Interferon-Alpha JO - Frontiers in Cellular and Infection Microbiology UR - https://www.frontiersin.org/articles/10.3389/fcimb.2021.656393 VL - 11 SN - 2235-2988 N2 - Sustained virologic response (SVR) in chronic hepatitis C (CHC) treatment denotes that the host genetics controls the immune response and unequivocally contribute to viral clearance or disease severity. In this context, single nucleotide polymorphisms (SNPs) in the locus of interferon lambda 3 and 4 genes (IFNL3/4) have been important genetic markers of responsiveness to CHC as prognostic markers for the pegylated-Interferon-alpha/ribavirin (Peg-IFN-α/RBV). Here, we analyzed 12 SNPs at the IFNL3/4 region in 740 treatment-naïve patients with CHC infected with hepatitis C virus (HCV) genotypes 1, 2, or 3 treated with Peg-IFN-α/RBV. Individually, rs12979860-CC, rs8109886-CC, or rs8099917-TT were predictive markers of SVR, while rs12979860-CC demonstrated the stronger effect. Besides, the genotypic combination of these three predictors’ genotypes, CC/CC/TT, increased the rate of SVR. Serum levels of cytokines and gene expression analysis on the genes IFNL3, IFNL4, IFNA1, and some of the IFN-stimulated genes (ISGs) were measured in a subgroup of 24 treated patients and 24 healthy volunteers. An antagonist effect was highlighted between the expression of IFNL3/4 and IFNA1 mRNA among patients. Besides, a prominent production of the pro-inflammatory chemokines CCL4 and CXCL10 was observed at a 12-week treatment follow-up. Lower serum levels of these chemokines were detected in patients with an rs12979860-CC genotype associated with the better treatment outcome. Also, lower expression levels of the IFI6, IFI16, IRF9 genes were observed among rs12979860-CC individuals. In conclusion, a combination of the genotypes at the IFNL3/4 locus can act as a better marker for the prognosis for virological responses in an admixed Brazilian population presenting the modulating effect over innate immunity and inflammation that are controlling the outcome of the viral infection, but also other infectious diseases. This study is registered on the ClinicalTrials.gov platform (accession number NCT01889849 and NCT01623336). ER -