Hepatitis B virus persistence after recovery from acute viral hepatitis.

Cytotoxic T lymphocytes (CTL) are thought to contribute to viral clearance and liver cell injury during hepatitis B virus (HBV) infection. Using a strategy involving the in vitro stimulation of peripheral blood mononuclear cells (PBMC) with HBV-derived synthetic peptides containing HLA-A2.1, -A31, and -Aw68 binding motifs, we have previously described CTL responses to several epitopes within the HBV nucleocapsid and envelope antigens in patients with acute hepatitis. In this study we define six HLA-A2-restricted CTL epitopes located in the highly conserved reverse transcriptase and RNase H domains of the viral polymerase protein, and we show that the CTL response to polymerase is polyclonal, multispecific, and mediated by CD8+ T cells in patients with acute viral hepatitis, but that it is not detectable in patients with chronic HBV infection or uninfected healthy blood donors. Importantly, the peptide-activated CTL recognize target cells that express endogenously synthesized polymerase protein, suggesting that these peptides represent naturally processed viral epitopes. DNA sequence analysis of the viruses in patients who did not respond to peptide stimulation indicated that CTL nonresponsiveness was not due to infection by viral variants that differed in sequences from the synthetic peptides. CTL specific for one of the epitopes were unable to recognize several naturally occurring viral variants, except at high peptide concentration, underlining the HBV subtype specificity of this response. Furthermore, CTL responses against polymerase, core, and envelope epitopes were detectable for more than a year after complete clinical recovery and seroconversion, reflecting either the persistence of trace amounts of virus or the presence of long lived memory CTL in the absence of viral antigen. Finally, we demonstrated that wild type viral DNA and RNA can persist indefinitely, in trace quantities, in the serum and PBMC after complete clinical and serological recovery, despite a concomitant, vigorous, and sustained polyclonal CTL response. Since viral persistence is not due to escape from CTL recognition under these conditions, the data suggest that HBV may retreat into immunologically privileged sites from which it can seed the circulation and reach CTL-inaccessible tissues, thereby maintaining the CTL response in apparently cured individuals and, perhaps, prolonging the liver disease in patients with chronic hepatitis.

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HLA-A31- and HLA-Aw68-restricted cytotoxic T cell responses to a single hepatitis B virus nucleocapsid epitope during acute viral hepatitis.

Journal of Experimental Medicine ◽

10.1084/jem.177.3.751 ◽

1993 ◽

Vol 177 (3) ◽

pp. 751-762 ◽

Cited By ~ 148

Author(s):

G Missale ◽

A Redeker ◽

J Person ◽

P Fowler ◽

S Guilhot ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Viral Hepatitis ◽

Acute Viral Hepatitis ◽

Hbv Infection ◽

Cytotoxic T Cell ◽

Core Antigen ◽

Binding Motif ◽

Ctl Response ◽

B Virus

We have recently developed the technology to identify and characterize the human histocompatibility leukocyte antigen (HLA) class I-restricted, CD8+ cytotoxic T lymphocyte (CTL) response to hepatitis B virus (HBV)-encoded antigens in patients with acute viral hepatitis. CTL are expanded in vitro by stimulation with HBV-derived synthetic peptides and selected by restimulation with a panel of HLA-matched stable transfectants that express the corresponding HBV protein. We have recently reported the existence of an HLA-A2-restricted, CD8+ CTL response to an epitope located between residues 18 and 27 of the HBV nucleocapsid core antigen (HBcAg). We now report the discovery of a CTL epitope located between HBcAg residues 141 and 151 that completely overlaps a critical domain in the viral nucleocapsid protein that is essential for its nuclear localization and genome packaging functions as well as processing of the precore protein. The CTL response to this epitope is dually restricted by the HLA-A31 and HLA-Aw68 alleles, which, unexpectedly, appear to use a common binding motif based on the results of alanine substitution and competition analysis, and the binding properties of these two alleles predicted from their known primary sequence, and from the three-dimensional structure of HLA-Aw68. We have also demonstrated that the HBV-specific CTL response to this epitope is polyclonal during acute viral hepatitis, since these two restriction elements can present the HBcAg 141-151 epitope to independent CTL clones derived from a single patient; and that the CTL response is multispecific, since HLA-A2-restricted and HLA-Aw68-restricted CTL responses to HBcAg 18-27 and HBcAg 141-151, respectively, have been identified to coexist in another patient. The foregoing argue against the emergence of CTL escape mutants as a significant problem during HBV infection, especially at this locus, where mutations might be incompatible with viral replication. Finally, our data suggest an association between the HBV-specific CTL response and viral clearance, and they have implications for the design of immunotherapeutic strategies to terminate HBV infection in chronically infected patients.

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Acute viral hepatitis in chronic carriers of hepatitis B virus: Different patterns in different places

Hepatology ◽

10.1002/hep.1840100220 ◽

1989 ◽

Vol 10 (2) ◽

pp. 252-253 ◽

Cited By ~ 2

Author(s):

Anna Lok

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Viral Hepatitis ◽

Acute Viral Hepatitis ◽

B Virus

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The efficacy of lamivudine in acute viral hepatitis with hepatitis B virus

Journal of Hepatology ◽

10.1016/s0168-8278(01)80525-0 ◽

2001 ◽

Vol 34 (0) ◽

pp. 144

Author(s):

C Apostolescu

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Viral Hepatitis ◽

Acute Viral Hepatitis ◽

B Virus

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The efficacy of lamivudine in acute viral hepatitis with hepatitis B virus

Journal of Hepatology ◽

10.1016/s0168-8278(01)81400-8 ◽

2001 ◽

Vol 34 ◽

pp. 144 ◽

Cited By ~ 1

Author(s):

C.G. Apostolescu ◽

I. Rebedea ◽

G. Coltan ◽

S.A. Iacob ◽

F.A. Caruntu

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Viral Hepatitis ◽

Acute Viral Hepatitis ◽

B Virus

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HIF1α‐mediated RelB/APOBEC3B downregulation allows Hepatitis B Virus persistence

Hepatology ◽

10.1002/hep.31902 ◽

2021 ◽

Author(s):

Tobias Riedl ◽

Suzanne Faure‐Dupuy ◽

Maude Rolland ◽

Svenja Schuehle ◽

Zohier Hizir ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Virus Persistence ◽

B Virus

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Viral Hepatitis: 1985 Update

Pediatrics in Review ◽

10.1542/pir.7.1.3 ◽

1985 ◽

Vol 7 (1) ◽

pp. 3-11

Author(s):

Saul Krugman

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Viral Hepatitis ◽

Hepatitis A ◽

Viral Infections ◽

Hepatitis A Virus ◽

Fatal Outcome ◽

Specific Marker ◽

Hepatitis D ◽

B Virus

During the past two decades extraordinary advances in hepatitis research have clarified the etiology and natural history of the disease. At least four types of hepatitis have been identified: A, B, D (delta), and non-A, non-B. Hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis D virus (HDV) have been characterized. Serologic tests have been developed to detect the antigens and antibodies associated with these three hepatitis infections. As of the present time, the non-A, non-B viral agents have not been identified. Therefore, non-A, non-B hepatitis is diagnosed by excluding other viral causes of hepatitis, such as hepatitis A virus, hepatitis B virus, Epstein-Barr virus (EBV), cytomegalovirus (CMV), and others. A recent report indicating that non-A, non-B hepatitis may be caused by a retrovirus, if confirmed, may provide a specific marker of this infection. The course of viral hepatitis is variable; it may be an asymptomatic, anteric infection, or it may be an acute illness characterized by fever, malaise, anorexia, nausea, abdominal pain, and jaundice. Most patients recover completely, but occasionally the infection may be complicated by chronic hepatitis, cirrhosis, and, occasionally, by a fulminant fatal outcome. This review will be devoted predominantly to a discussion of the diagnostic and prophylactic aspects of hepatitis A and hepatitis B viral infections.

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