39 Low doses of hepadnavirus induce infection of the lymphatic system that does not engage the liver

Abstract

Woodchuck hepatitis virus (WHV), which is closely related to human hepatitis B virus and is considered to be principally hepatotropic, invades the host's lymphatic system and persists in lymphoid cells independently of whether the infection is symptomatic and serologically evident or concealed. In this study, we show, with the woodchuck model of hepatitis B, that hepadnavirus can establish an infection that engages the lymphatic system, but not the liver, and persists in the absence of virus serological markers, including antiviral antibodies. This primary occult infection is caused by wild-type virus invading the host at a quantity usually not greater than 10 3 virions. It is characterized by trace virus replication progressing in lymphatic organs and peripheral lymphoid cells that, with time, may also spread to the liver. The infection is transmissible to virus-naive hosts as an asymptomatic, indefinitely long, occult carriage of small amounts of biologically competent virus. In contrast to residual silent WHV persistence, which normally endures after the resolution of viral hepatitis and involves the liver, primary occult infection restricted to the lymphatic system does not protect against reinfection with a large, liver-pathogenic WHV dose; however, the occult infection is associated with a swift recovery from hepatitis caused by the superinfection. Our study documents that the lymphatic system is the primary target of WHV infection when small quantities of virions invade a susceptible host.Replication and retention of virus in cells of the immune system characterize many persistent viral infections and are a major hindrance to sterilizing antiviral therapy. Human hepatitis B virus (HBV) and its close relative woodchuck hepatitis virus (WHV), infecting the eastern American woodchuck (Marmota monax), are noncytopathic hepadnaviruses which cause similar courses and outcomes of liver disease (7,27,29,41,42). It is estimated that 350 to 400 million people worldwide are chronically infected with HBV (43). This lifelong infection, with which the patient is serologically HBV surface antigen (HBsAg) reactive, is accompanied by chronic hepatitis that frequently advances to cirrhosis and hepatocellular carcinoma (HCC). It is now evident that HBV also elicits occult long-term persistence, as has been determined from the detection of the virus by HBV DNA PCR but not by the current and otherwise sensitive immunoassays for HBsAg (1-3, 7, 10, 22, 25, 34, 36, 38, 45, 46). The epidemiological and pathogenic importance of this silent HBV carriage is increasingly evident, particularly in regard to (i) the transmission of virus traces through seemingly HBV-negative blood transfusion, hemodialysis, or organ transplantation (5, 12, 37); (ii) cytotoxic or immunosuppressive therapy (13, 24); and (iii) the pathogenesis of liver diseases considered to be cryptogenic, e.g., HCC (4,6,21,44). In the woodchuck model of hepatitis B, which is the closest natural animal model for the study of HBV pathobiology (27,29,41,42), the lifelong s...