Abstract
Hepatitis B virus (HBV) chronically infects over 250 million people worldwide and causes nearly 1 million deaths per year due to cirrhosis and liver cancer. Approved treatments for chronic infection include injectable type-I interferons and nucleos(t)ide reverse transcriptase inhibitors. A small minority of patients achieve seroclearance after treatment with type-I interferons, defined as sustained absence of detectable HBV DNA and surface antigen (HBsAg) antigenemia. However, type-I interferons cause significant side effects, are costly, must be administered for months, and most patients have viral rebound or non-response. Nucleos(t)ide reverse transcriptase inhibitors reduce HBV viral load and improve liver-related outcomes, but do not lower HBsAg levels or impart seroclearance. Thus, new therapeutics are urgently needed. Lambda interferons (IFNLs) have been tested as an alternative strategy to stimulate host antiviral pathways to treat HBV infection. IFNLs comprise an evolutionarily conserved innate immune pathway and have cell-type specific activity on hepatocytes, other epithelial cells found at mucosal surfaces, and some immune cells due to restricted cellular expression of the IFNL receptor. This article will review work that examined expression of IFNLs during acute and chronic HBV infection, the impact of IFNLs on HBV replication in vitro and in vivo, the association of polymorphisms in IFNL genes with clinical outcomes, and the therapeutic evaluation of IFNLs for the treatment of chronic HBV infection.
Highlights
Lambda InterferonsInterferons (IFNs) are a class of cytokines that play a key role in antiviral defense [22,23]
Hepatitis B virus (HBV) chronically infects over 250 million people worldwide and causes nearly 1 million deaths per year due to cirrhosis and liver cancer
The association of IFNL polymorphisms with HBV infection outcomes and response to IFN-based treatment is either absent or weaker than the association observed with hepatitis C virus (HCV)
Summary
Interferons (IFNs) are a class of cytokines that play a key role in antiviral defense [22,23]. Type-III or lambda IFNs (IFNLs) were first discovered in 2003 as a novel family of cytokines that induce a transcriptional program similar to type-I IFNs [23,27,28,29], but by signaling through a distinct receptor complex. Type-I IFNs signal through a heterodimeric receptor composed of interferon receptor alpha-1 (IFNAR1) and IFNAR2, which are expressed on the surface of most cells [23,30,31,32]. IFNLs signal through a heterodimeric receptor composed of interferon lambda receptor-1 (IFNLR1) and interleukin-10 receptor subunit beta (IL10RB) [28,33,34,35]. A dinucleotide polymorphism within an exon of IFNL4 imparts differential capacity to make IFNL4 protein, such that some individuals are Viruses 2021, 13, 1090 incapable of making functional IFNL4 [45], whereas all people can make IFNL1, IFNL2, and IFNL3
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