Identification and transmission of hepatitis B virus-related variants.

Abstract

We have identified long-incubation viral agents that share epitopes with hepatitis B virus (HBV). During chimpanzee infectivity studies, these agents may be recognized in the liver since they possess complementary nucleic acid sequences with HBV DNA; the genomic size was found to be 3.2 kilobases, identical to that of HBV. Liver injury was produced and there was antigen expression in hepatocytes. Chimpanzees were not protected by prior immunization with hepatitis B surface antigen; conversely, they were still susceptible to HBV after recovery from infection with such agents. These findings suggest that these hepatitis B virus-related variants appear to be immunologically distinct from HBV.Previous studies on sera using monoclonal anti-hepatitis B surface antigen antibody (anti-HBsAg) radioimmunoassays (M-RIAs) have established that there are individuals with acute and chronic hepatitis infection and hepatocellular carcinoma whose serum demonstrates positive binding activity only in these tests (1-8). Such patients were found to be negative for hepatitis B surface antigen (HBsAg) by polyclonal anti-HBsAg RIA (P-RIA) and some lacked evidence of recent or past exposure to hepatitis B virus (HBV) as shown by the absence of antibodies to the core (antiHBcAg) and to surface antigens (anti-HBsAg) in the blood (4-8). HBV DNA hybridizable sequences were detected in the liver and serum ofa significant number of such individuals and this finding correlated with the detection of antigen in serum by 6). However, very little is known regarding the biologic properties and characteristics of the M-RIA HBV DNA-positive agents in serum. We report here the identification, transmission, and partial characterization of some viral agents during chimpanzee infectivity studies. These hepatitis viral variants appear to be antigenically related to and share nucleic acid homology with HBV. His serum was negative for HBsAg, anti-HBsAg and antiHBcAg antibodies by P-RIAs but was found to be reactive at a S/N ratio of 24.0 by M-RIA, and HBV DNA complementary sequences were detected by dot blot analysis. METHODSTwo chimpanzees (Dolf and lanthe) were previously immunized with a yeast recombinant HBV DNA-derived HBsAg vaccine. These chimpanzees had been subsequently challenged with a standard National Institutes ofHealth HBV inoculum known to produce infection in unimmunized chimpanzees; both animals were found to be protected from HBV infection. The details of these experiments have been reported elsewhere (9). Two other chimpanzees (Sjef and Jimmie) had not been previously exposed to HBV or to the non-A, non-B hepatitis agents, and their serum was negative for HBsAg, anti-HBsAg, and anti-HBcAg antibodies. In contrast, Dolf and Ianthe had high titer anti-HBsAg antibodies as the result of past vaccination with HBsAg; anti-HBcAg antibodies, however, were not present. lanthe and Sjef were inoculated intravenously with 3 ml of serum M, and Jimmie and Dolf were inoculated with 3 ml of serum G. After injection of serum, the chimpanzees were s...

Sero-clearance of hepatitis B surface antigen in chronic carriers does not necessarily imply a good prognosis

“…Moreover, the antigen could be hidden in HBsAg-anti-HBs immune complexes, or an HBV variant with different viral antigenicity and immunogenicity may exist as described elsewhere. 37,38 It was reported that among 30 anti-HCV-positive HBsAg-clearance patients (with or without elevation of serum ALT), HBV DNA could not be detected even with the PCR method. 27 In contrast, four anti-HCV-positive patients still had detectable HBV DNA in our study.…”

Persistent Hepatitis B Virus Infection in Subjects Without Hepatitis B Surface Antigen: Clinically Significant or Purely “Occult”?

“…14,15,63 Similar observations were made during transmission experiments in chimpanzees. 13 It is still plausible that the observed hepatitis may be due to a presently unknown associated virus or to nonviral-related disturbances; yet such temporal associations clearly suggest a potential direct pathogenic role for the HBV particles. In this view, it is plausible that, despite low HBV viremia, such pathogenic effects may be enhanced by the large volume of blood transfused.…”

“…The presence of complete infectious HBV particles in these patients was established using several complementary approaches: the transmission of hepatitis by HBV-DNA-positive sera into chimpanzees 13,14 ; post-transfusional and mother-tochild transmission of HBV DNA 14,15 ; the reinfection of liver grafts after liver transplantation for HBsAg-negative cirrhosis 16,17 ; and infection arising from HBsAg-negative organ donors. [18][19][20][21] These observations have been confirmed by reports of viral RNAs (including the viral pregenome) and covalently closed circular HBV DNA in the liver of these patients.…”

Global control of hepatitis B virus: does treatment-induced antigenic change affect immunization?

“…11 Mutations in and around the "a" determinant may lead to an alteration in the antigenicity of the surface antigen protein so that antibodies directed against the surface antigen protein may fail to neutralize the virus. [12][13][14][15][16][17][18][19][20] Infection of immunized individuals with a vaccine escape mutant (VEM) 20 is therefore possible. VEMs are typically characterized by the presence of single-amino-acid changes in the S protein.…”