Review of Lambda Interferons in Hepatitis B Virus Infection: Outcomes and Therapeutic Strategies

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.

Keywords: hepatitis B virus; innate immunity; interferon lambda; seroclearance.

Figure 1

Proposed models and selected mechanisms for HBV suppression or evasion of the host innate immune response in hepatocytes. (A) HBV is recognized by the host cell, an antiviral response is induced including expression of IFNLs, but this response is subsequently suppressed by viral elements. (B) HBV is not sensed by the host cell and IFNLs are not produced even though detection and signaling proteins are functional. Exposure of HBV-infected hepatocytes to endogenous IFNLs can overcome immune inactivity. Figure created with BioRender.com.