AUTHOR=Silva Andréa Marques Vieira da , Alvarado-Arnez Lucia Elena , Azamor Tamiris , Batista-Silva Leonardo Ribeiro , Leal-Calvo Thyago , Bezerra Ohanna Cavalcanti de Lima , Ribeiro-Alves Marcelo , Kehdy Fernanda de Souza Gomes , Neves Patrícia Cristina da Costa , Bayma Camilla , Silva Jane da , Souza Alessandro Fonseca de , Muller Marcelo , Andrade Elisabete Ferreira de , Andrade Ana Carolina Magalhães , Santos Eliane Matos dos , Xavier Janaína Reis , Maia Maria De Lourdes De Sousa , Meireles Rolando Páez , Cuni Hugo Nodarse , Sander Guilherme Becker , Picon Paulo Dornelles , Matos Denise C S , Moraes Milton Ozório 

TITLE=Interferon-lambda 3 and 4 Polymorphisms Increase Sustained Virological Responses and Regulate Innate Immunity in Antiviral Therapy With Pegylated Interferon-Alpha

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2021.656393

DOI=10.3389/fcimb.2021.656393

ISSN=2235-2988

ABSTRACT=<p>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 (<italic>IFNL3/4</italic>) 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 <italic>IFNL3/4</italic> 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 <italic>IFNL3</italic>, <italic>IFNL4</italic>, <italic>IFNA1</italic>, 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 <italic>IFNL3/4</italic> and <italic>IFNA1</italic> 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 <italic>IFI6</italic>, <italic>IFI16</italic>, <italic>IRF9</italic> genes were observed among rs12979860-CC individuals. In conclusion, a combination of the genotypes at the <italic>IFNL3/4</italic> 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).</p>