Traces of hepatitis B virus (HBV) genome can persist for years following recovery from hepatitis B. To determine overall duration, molecular characteristics, and pathological implications of this serologically undetectable form of hepadnaviral carriage, we have analyzed the expression of transcriptionally active virus genomes, their infectivity, and examined liver alterations during the natural lifespan of woodchucks convalescent from acute infection with HBVrelated woodchuck hepatitis virus (WHV). In this study, we document lifelong persistence of scanty amounts of replicating virus both in the liver and lymphatic system after spontaneous resolution of an episode of experimental hepadnaviral hepatitis. Antibodies to virus nucleocapsid (core) were found to be the most reliable immunovirological marker coexisting with occult infection. In the majority of convalescent woodchucks, serial liver biopsies showed protracted minimal to mild necroinflammation with periods of normal morphology; however, hepatocellular carcinoma (HCC) ultimately developed in 2 of 9 animals studied. Inocula derived from lymphoid cells of convalescent animals induced classical acute hepatitis in virus-naive woodchucks that progressed to chronic hepatitis and HCC in 1 of the animals, demonstrating infectivity and pathogenic competence of the carried virus. Our results reveal that low levels of infectious WHV and residual hepatic inflammation usually continue for life after resolution of hepatitis and that this recovery does not avert HCC development. They also demonstrate that, in addition to the liver, the lymphatic system is the site of the occult lifelong maintenance of replicating hepadnavirus. (HEPATOLOGY 1999;29:928-938.)Current evidence indicates that carriage of minute quantities of hepatitis B virus (HBV) genome can continue for years following complete clinical and serological recovery from acute hepatitis B. 1-5 In these convalescent patients, HBV DNA have been detected both in serum and in circulating lymphomononuclear cells, often despite the presence of neutralizing antibodies to virus envelope (hepatitis B surface antigen) 2,3,5 and a vigorous polyclonal HBV-specific cytotoxic T-cell response. 3,4,6 In addition, traces of hepatitis B surface antigen and HBV-DNA-reactive particles with physicochemical properties of intact virions have been detected in the circulation of some of the recovered individuals. 2 These findings imply that HBV eradication does not coincide with the rise of antivirusspecific humoral and cellular immune responses and with clinical resolution of acute hepatitis.It is expected that this serologically undetectable persistence of HBV may have important epidemiological and pathogenic implications, whose range has yet to be established. This assumption is based on a growing number of observations indicating that HBV infection can appear in recipients of organs from HBV serologically negative donors, [7][8][9][10][11][12] and that hepatocellular carcinoma (HCC) with integrated HBV genomic sequences can arise in ...

The incidence of PLA is increasing and is associated with significant mortality that is attributable to several modifiable risk factors.

Mother-to-child transmission is an important route for hepatitis B virus (HBV) dissemination. It has been established that HBV traces persist for years after complete clinical recovery from hepatitis B. Similarly, resolution of hepatitis caused by HBV-related woodchuck hepatitis virus (WHV) is followed by occult lifelong carriage of pathogenic virus. In this study, we documented that WHV persisting after termination of acute hepatitis is transmittable to newborns as an asymptomatic long-term infection. All 11 offspring from 4 dams studied carried transcriptionally active WHV genomes for 3.5 years after birth without immunovirological markers of infection. WHV genomes and mRNA were detected both in the liver and lymphoid tissue in the majority of offspring; WHV covalently closed circular DNA was detected in some samples. In 4 offspring, however, the virus was restricted to the lymphatic system. In the circulation, WHV DNA-reactive particles were DNase resistant and of comparable size and density to complete virions. Importantly, the virus in offspring with or without hepatic WHV DNA expression was infectious to WHV-naive woodchucks. Finally, offspring challenged with WHV were not protected against reinfection. These findings show that mothers with occult hepadnaviral carriage transmit pathogenic virus to their offspring, inducing a persistent infection invariably within the lymphatic system but not always in the liver.

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...