The IFNL3 gene, or Interferon Lambda 3, is a component of the body’s innate immune system, acting as a first line of defense against invading pathogens. It was initially identified as IL28B, but its nomenclature was updated to reflect its classification as a Type III interferon. This gene family shares functional similarities with Type I interferons, such as IFN-alpha, but their effects are concentrated in specific tissues. The structure of the IFNL3 gene, along with its close relatives IFNL1 and IFNL2, is clustered on the long arm of human chromosome 19 at position 19q13. This gene encodes a protein also called Interferon Lambda 3, which is a signaling molecule belonging to the Class II cytokine family.
The Structure and Polymorphisms of IFNL3
The physical makeup of the IFNL3 gene includes a region studied for minor genetic variations called Single Nucleotide Polymorphisms (SNPs). These SNPs are single-letter changes in the DNA sequence that create different versions, or genotypes, of the gene. The most widely studied SNP is rs12979860, located approximately 3 kilobases upstream of the IFNL3 gene. This marker involves a change from a Cytosine (C) to a Thymine (T) nucleotide, meaning an individual’s genotype can be CC, CT, or TT. The CC genotype is often referred to as the “favorable” or “responder” genotype, as these genetic differences impact the expression or function of the interferon protein.
The Role of Interferon Lambda 3 in Immunity
Interferon Lambda 3 (IFN-λ3) functions as a cytokine released by host cells in response to viral infection. Its primary role is to establish an antiviral state in surrounding cells as a component of the innate immune response. IFN-λ3 achieves this by binding to a specific receptor complex on the cell surface, composed of the IFN-lambda receptor 1 (IFNLR1) and the shared Interleukin 10 receptor beta (IL10RB). This binding activates the JAK-STAT signaling pathway, leading to the transcription of Interferon-Stimulated Genes (ISGs) that interfere with viral replication. A distinguishing feature is the restricted expression of IFNLR1, predominantly found on epithelial cells of mucosal surfaces and on hepatocytes in the liver, allowing for a localized antiviral response with less systemic inflammation compared to Type I interferons.
IFNL3 Genotype and Hepatitis C Treatment
The IFNL3 gene gained widespread recognition due to its powerful association with the outcome of Hepatitis C Virus (HCV) infection, particularly in the context of treatment. Before the advent of modern treatments, the standard of care for chronic HCV infection involved a combination of Pegylated-Interferon-alpha and ribavirin. The success of this older regimen was measured by achieving a Sustained Virological Response (SVR), defined as undetectable HCV RNA six months after the end of therapy.
Genetic testing for the IFNL3 rs12979860 SNP became a significant pretreatment predictor for SVR, especially in patients infected with HCV genotype 1. Patients carrying the CC genotype had a substantially higher likelihood of clearing the virus, often showing a nearly two-fold increase in SVR rates compared to those with the CT or TT genotypes. This genetic information was historically used by clinicians to stratify patients, determining who should be immediately treated.
The favorable CC genotype is associated not only with a better response to interferon-based therapy but also with a higher rate of spontaneous HCV clearance without any treatment. Allele frequencies of this SNP vary significantly across global populations, with the favorable CC variant being most common in East Asians and least common in individuals of African ancestry. Although the introduction of highly effective Direct-Acting Antivirals (DAAs) has rendered interferon-based regimens largely obsolete, the IFNL3 genotype still predicts response in certain DAA regimens and is a factor in determining optimal treatment duration for some patients.
Emerging Health Associations
The influence of IFNL3 extends beyond Hepatitis C, suggesting a broader role for Type III interferons in overall health and disease susceptibility. Variations in the IFNL3 locus have been linked to the outcome of other viral infections, including Hepatitis B Virus (HBV) and Human Immunodeficiency Virus (HIV). Research has also shown a connection between IFNL3 polymorphisms and the severity of certain respiratory infections, such as COVID-19, where the favorable CC genotype was associated with better outcomes.
The gene’s role in regulating the immune response also connects it to chronic inflammatory conditions and cancer. Studies have explored associations between IFNL3 variants and autoimmune diseases like inflammatory bowel disease and psoriasis. The less favorable T allele of the rs12979860 SNP, for instance, has been associated with an elevated risk of hepatocellular carcinoma (HCC) in patients with chronic HCV infection. These ongoing investigations demonstrate the IFNL3 gene’s importance as a general regulator of host-virus interactions and immune-mediated health outcomes.