Lu Yi-Fan, Goldstein David B, Urban Thomas J, Bradrick Shelton S
Department of Molecular Genetics and Microbiology, Duke University Medical Center, NC 27710, USA; Center for Human Genome Variation, Duke University Medical Center, NC 27710, USA.
Center for Human Genome Variation, Duke University Medical Center, NC 27710, USA.
Virology. 2015 Feb;476:334-340. doi: 10.1016/j.virol.2014.12.020. Epub 2015 Jan 9.
Genetic variants surrounding the interferon-λ3 (IFNL3) gene are strongly associated with clearance of hepatitis C virus (HCV). A variant (rs368234815 TT/ΔG) upstream of IFNL3 was recently implicated to control expression of a novel gene termed IFNL4. We conducted genetic analysis of rs368234815 in a chronic HCV patient cohort and molecular studies of IFNL4 in primary human hepatocytes (PHHs). Analysis of PHHs that are heterozygous at rs368234815 revealed that the IFNL4 transcript isoform is rare, accounting for 2% of transcripts arising from the IFNL4 locus. Nevertheless, IFNL4 over-expression inhibited replication of multiple Flaviviridae and IFNL4 anti-viral potency required the IFNL receptor. In contrast to IFNL3, IFNL4 was inefficiently secreted and appeared to act in a cell-autonomous manner. Genetic analysis revealed associations of rs368234815 with sustained virological response and pre-treatment viral load. The findings suggest that IFNL4 is an atypical IFNL whose activity may be maladaptive to clearance of HCV infection.
干扰素-λ3（IFNL3）基因周围的遗传变异与丙型肝炎病毒（HCV）的清除密切相关。最近发现IFNL3上游的一个变异（rs368234815 TT/ΔG）可调控一个名为IFNL4的新基因的表达。我们对慢性HCV患者队列中的rs368234815进行了基因分析，并在原代人肝细胞（PHH）中对IFNL4进行了分子研究。对rs368234815杂合的PHH分析显示，IFNL4转录本异构体很少见，占IFNL4基因座产生的转录本的2%。然而，IFNL4的过表达抑制了多种黄病毒科病毒的复制，且IFNL4的抗病毒效力需要IFNL受体。与IFNL3不同，IFNL4分泌效率低下，似乎以细胞自主方式发挥作用。基因分析揭示了rs368234815与持续病毒学应答和治疗前病毒载量的关联。这些发现表明，IFNL4是一种非典型的IFNL，其活性可能不利于HCV感染的清除。
