Fine specificity of the human T-cell response to the hepatitis B virus preS1 antigen

Ferrari, Carlo; Cavalli, A.; Penna, Amalia; Valli, A; Bertoletti, Antonio; Pedretti, Giorgio; Pilli, Massimo; Vitali, P; Neri, Tauro Maria; Giuberti, T.; Fiaccadori, F

doi:10.1016/0016-5085(92)91121-j

Cited by 48 publications

(30 citation statements)

References 18 publications

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“…The vaccine-induced T-cell responses to WHsAg in serum from woodchucks were essentially polyclonal, a result which is analogous to those for human vaccine recipients receiving HBsAg vaccines (5,13,15,19). The WHs-specific T-cell responses observed for outbred, WHV-negative woodchucks were directed against several fairly dominant sites (epitopes), each of which probably plays a role in vaccine protection, and correlate with recovery from WHV infection.…”

Section: Discussionmentioning

confidence: 60%

Chemoimmunotherapy of Chronic Hepatitis B Virus Infection in the Woodchuck Model Overcomes Immunologic Tolerance and Restores T-Cell Responses to Pre-S and S Regions of the Viral Envelope Protein

Menne

Tennant

Gerin

et al. 2007

J Virol

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Treatment of chronic hepatitis B virus (HBV) infection could combine potent antiviral drugs and therapeuticvaccines to overcome immunological tolerance and induce the recovery phenotype to protect against disease progression. Conventional vaccination of woodchucks chronically infected with the woodchuck hepatitis virus (WHV) elicited differential T-cell response profiles depending on whether or not carriers were treated with the potent antiviral drug clevudine (CLV), which significantly reduces viral and antigen loads. The differential T-cell responses defined both CLV-dependent and CLV-independent epitopes of the pre-S and S regions of the WHV envelope protein. Only combined treatment involving CLV and conventional vaccine therapeutically restored the T-cell response profile of chronic WHV carrier woodchucks to that seen in prophylactic vaccination and in recovery from acute WHV infection. The results have implications for mechanisms of immunological tolerance operating in chronic HBV infection and suggest that such combined chemoimmunotherapy may be useful for treatment of humans with chronic HBV infection. Chronic hepatitis B virus (HBV) infection is often associatedwith immunological tolerance to the virus characterized by hyporesponsive T helper (Th) cells, reduced numbers of cytolytic T lymphocytes, diminished Th1-type cytokine responses, and undetectable virus-neutralizing antibodies to viral envelope proteins (3,8,9,16,20,24,27,42, 46). When HBVspecific cellular immune responses sometimes become detectable in HBV carriers, they are often suboptimal and contribute more to disease progression than to viral clearance and recovery (8,16,27, 46). Immunological tolerance in chronic HBV infection (2,4,6,7,37,38) may arise theoretically from central or peripheral tolerance mechanisms (or both). Central tolerance could involve negative selection of antigen-specific T cells by thymic deletion in the presence of antigen (6,7,37,38). Peripheral tolerance may follow after positive selection of antigen-specific T cells and result from clonal anergy, immunological exhaustion, or altered regulation between Th1 and Th2 cells (1, 43). The development and/or maintenance of central and peripheral tolerance in chronic HBV infection may be a consequence of the high viral and antigen loads often observed in chronic carriers. The development of immunotherapeutics able to circumvent T-cell tolerance, alone or in combination with antiviral therapeutics, represents a further critical step toward the successful treatment of chronic HBV infection.Vaccines for HBV will ultimately interdict transmission of the virus and eradicate HBV-related diseases. However, there are currently more than 350 million chronic carriers of HBV worldwide who are at risk of developing chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) (47). Treatment options for chronic HBV infection are limited presently. Pegylated alpha interferon brings about sustained antiviral responses in approximately one-third of patients (25) but is associated with ...

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Section: Discussionmentioning

confidence: 60%

Chemoimmunotherapy of Chronic Hepatitis B Virus Infection in the Woodchuck Model Overcomes Immunologic Tolerance and Restores T-Cell Responses to Pre-S and S Regions of the Viral Envelope Protein

Menne

Tennant

Gerin

et al. 2007

J Virol

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“…The pre-S1 and pre-S2 regions play an essential role in the interaction with immune responses because they contain several epitopes for T or B cells [22], [23]. Pre-S deletion decreases the expression of surface proteins of HBV, resulting in intracellular accumulation of HBV envelope proteins and viral particles, formation of ground glass hepatocytes, inducing endoplasmic reticulum stress and oxidative DNA damage, and eventually hepatocellular carcinogenesis [12], [15].…”

Section: Discussionmentioning

confidence: 99%

Association of Hepatitis B Virus Pre-S Deletions with the Development of Hepatocellular Carcinoma in Qidong, China

Liu

et al. 2014

PLoS ONE

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Background/AimTo investigate the roles of mutations in pre-S and S regions of hepatitis B virus (HBV) on the progression of hepatocellular carcinoma (HCC) in Qidong, China.MethodsWe conducted an age matched case-control study within a cohort of 2387 male HBV carriers who were recruited from August, 1996. The HBV DNA sequence in pre-S/S regions was successfully determined in 96 HCC cases and 97 control subjects. In addition, a consecutive series of samples from 11 HCC cases were employed to evaluate the pre-S deletion patterns before and after the occurrence of HCC.ResultsAfter adjustment for age, history of cigarette smoking and alcohol consumption, HBeAg positivity, pre-S deletions, pre-S2 start codon mutations, and T53C mutation were significantly associated with HCC, showing adjusted odds ratios (ORs) from 1.914 to 3.199. HCC patients also had a lower frequency of T31C mutation in pre-S2 gene, compared with control subjects (0.524; 95% CI 0.280-0.982). HBV pre-S deletions were clustered mainly in the 5′ end of pre-S2 region. Multivariate analysis showed that pre-S deletions and pre-S2 start codon mutations were independent risk factors for HCC. The OR (95% CI) were 2.434 (1.063–5.573) and 3.065 (1.099–8.547), respectively. The longitudinal observation indicated that the pre-S deletion mutations were not acquired at the beginning of HBV infection, but that the mutations occurred during the long course of liver disease.ConclusionPre-S deletions and pre-S2 start codon mutations were independently associated with the development of HCC. The results also provided direct evidence that pre-S deletion mutations were not acquired from the beginning of infection but arose de novo during the progression of liver disease.

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“…The HBV envelope is composed of 3 forms of HBV surface antigen: large (coded for by the pre-S1/pre-S2/S gene), middle (the preS2/S gene), and small (the S gene) protein. The pre-S regions play an essential role in the interaction with the immune responses because they contain several epitopes for T or B cells [25], [26]. In persistent HBV infection, immune epitope deletion mutants occur, escape the host immune surveillance, and lose important functional sites.…”

Section: Discussionmentioning

confidence: 99%

Pre-S Deletion and Complex Mutations of Hepatitis B Virus Related to Young Age Hepatocellular Carcinoma in Qidong, China

Kuai

Liu

et al. 2013

PLoS ONE

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Background/AimTo investigate the roles of biomedical factors, hepatitis B virus (HBV) DNA levels, genotypes, and specific viral mutation patterns on the progression of hepatocellular carcinoma (HCC) patients below 40 years of age in Qidong, China.MethodsWe conducted a case-control study within a cohort of 2387 male HBV carriers who were recruited from August, 1996. The HBV DNA sequence was determined in 49 HCC and 90 chronic hepatitis (CH) patients below 40 years of age. Mutation exchanges during follow-up in 32 cases were compared with 65 controls with paired serum samples. In addition, a consecutive series of samples from 14 HCC cases were employed to compare the sequences before and after the occurrence of HCC.ResultsAfter adjustment for age, history of cigarette smoking and alcohol consumption, HBeAg positive, HBV DNA levels ≥4.00 log10 copies/mL, pre-S deletion, T1762/A1764 double mutations, and T1766 and/or A1768 mutations were associated with risk of young age HCC. Moreover, the presence of an increasing number of HCC-related mutations (pre-S deletion, T1762/A1764, and T1766 and/or A1768 mutations) was associated with an increased risk of young age HCC. Paired samples analysis indicated that the increased HCC risk for at-risk sequence mutations were attributable to the persistence of these mutations, but not a single time point mutation. The longitudinal observation demonstrated a gradual combination of pre-S deletion, T1762/A1764 double mutations, and T1766 and/or A1768 mutations during the development of HCC.ConclusionHigh HBV DNA levels and pre-S deletion were independent risk factors of young age HCC. Combination of pre-S deletion and core promoter mutations increased the risk and persistence of at-risk sequence mutations is critical for HCC development.

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Fine specificity of the human T-cell response to the hepatitis B virus preS1 antigen

Cited by 48 publications

References 18 publications

Chemoimmunotherapy of Chronic Hepatitis B Virus Infection in the Woodchuck Model Overcomes Immunologic Tolerance and Restores T-Cell Responses to Pre-S and S Regions of the Viral Envelope Protein

Chemoimmunotherapy of Chronic Hepatitis B Virus Infection in the Woodchuck Model Overcomes Immunologic Tolerance and Restores T-Cell Responses to Pre-S and S Regions of the Viral Envelope Protein

Association of Hepatitis B Virus Pre-S Deletions with the Development of Hepatocellular Carcinoma in Qidong, China

Pre-S Deletion and Complex Mutations of Hepatitis B Virus Related to Young Age Hepatocellular Carcinoma in Qidong, China

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