SUMMARY Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA-sequencing in primary human hepatocytes activated with synthetic dsRNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a novel, transiently induced region that harbors dinucleotide variant ss469415590 (TT/ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590-ΔG is a frame-shift variant that creates a novel primate-specific gene, designated interferon lambda 4 (IFNL4), which encodes a protein of moderate similarity with IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, whereas it provides comparable information in Europeans and Asians. Transient over-expression of IFNL4 in a hepatoma cell line induced STAT1/STAT2 phosphorylation and expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management.

More than 500 million people worldwide are persistently infected with the hepatitis B virus (HBV) and/or hepatitis C virus (HCV) and are at risk of developing chronic liver disease, cirrhosis and hepatocellular carcinoma. Despite many common features in the pathogenesis of HBV- and HCV-related liver disease, these viruses markedly differ in their virological properties and in their immune escape and survival strategies. This review assesses recent advances in our understanding of viral hepatitis, contrasts mechanisms of virus-host interaction in acute hepatitis B and hepatitis C, and outlines areas for future studies.

Anatomy of the Liver and Its Immune SystemThe structural organization of the liver has profound implications for its immune function. The liver's blood supply depends on a conventional arterial system from the abdominal aorta that supports predominantly bile ducts and other tissues in the portal tracts, and on two venous systems: a minor system from the arterial plexus within portal tracts (peribiliary plexus) and a major system from the splanchnic organs. About 30% of the total blood passes through the liver every minute 1 carrying about 10 8 peripheral blood lymphocytes in 24 hours. 2 Blood enters the hepatic parenchyma mainly via terminal portal vessels, then passes through a network of liver sinusoids, leaving the parenchyma via the central hepatic veins (Fig. 1). Due to the small diameter of the sinusoids, minimal increases in systemic venous pressure and perturbations of sinusoidal flow result in stasis, which lengthens the contact between lymphocytes and antigen-presenting cells and promotes lymphocyte extravasation. Extravasation is further facilitated by fenestrations in the monolayer of sinusoidal endothelial cells (LSEC) 3 that allow lymphocytes to access the space of Dissé via cytoplasmic extensions and to 'touch' the underlying extracellular matrix, stellate cells and hepatocytes.Hepatocytes constitute only about two thirds of the total cell population in the liver. The remaining population of nonparenchymal cells is diverse and includes LSEC, Kupffer cells, biliary cells, stellate (Ito or fat-storing) cells and intrahepatic lymphocytes (Fig. 2).Lymphocytes are found scattered throughout the parenchyma, as well as in the portal tracts. The average human liver contains a population of approximately 10 10 lymphocytes, which include conventional and unconventional lymphocyte subpopulations of the innate (NKT and NK cells) and adaptive immune systems (T and B cells), respectively (Fig. 2). Conventional T cells comprise CD8 ϩ and CD4 ϩ T cells. Both populations display a diverse repertoire of T cells with ␣␤-chain T cell receptors, that recognize antigens in the context of MHC class I and II molecules, respectively. CD8 ϩ T cells typically outnumber CD4 ϩ T cells in the liver and the frequency of effector/memory cells is higher than in the blood. Unconventional T cells comprise various cell types that are categorized into two major populations: those that express NK cell markers (also called NK T cells) and those that do not. The population of classical NKT cells arises in the thymus, displays a very restricted T cell receptor repertoire (typically the T cell receptor V␣24 and V␤11 chains in humans) and recognizes antigens in the context of the MHC class I molecule CD1d. While their natural antigen is not known, the marine sponge antigen alpha-