Preserved T-Cell Function in Children and Young Adults With Immune-Tolerant Chronic Hepatitis B

Kennedy, Patrick T.; Sandalova, Elena; Jo, Juandy; Gill, Upkar S.; Ushiro-Lumb, Inês; Tan, Anthony T.; Naik, Sandhia; Foster, Graham R.; Bertoletti, Antonio

doi:10.1053/j.gastro.2012.06.009

Cited by 262 publications

(213 citation statements)

References 26 publications

Supporting

Mentioning

194

Contrasting

Unclassified

Order By: Relevance

“…In these patients, normal or low levels of ALT and mild or no liver necroinflammation are observed, which is also a characteristic of our mouse model. Another feature of these patients is the apparent state of immune tolerance toward the virus, although this was revisited in a recent study (29). In our mice, neither HBc-nor HBs-specific T cells were detected in the periphery or the liver at either early or late time points after AAV2/8-HBV injection.…”

Section: Discussionmentioning

confidence: 56%

Adeno-Associated Virus-Mediated Gene Transfer Leads to Persistent Hepatitis B Virus Replication in Mice Expressing HLA-A2 and HLA-DR1 Molecules

Dion

Bourgine

Godon

et al. 2013

J Virol

100

125

View full text Add to dashboard Cite

H epatitis B virus (HBV) infection is a major health problem.There are more than 350 million chronic carriers worldwide, and they are at high risk of developing liver cirrhosis and hepatocellular carcinoma (1). Chronic HBV infection is the result of impaired HBV-specific immune responses such that the infected hepatocytes cannot be eliminated or cured efficiently, but many of the associated issues remain unclear (2, 3).Due to the paucity of in vitro and in vivo models for HBV infection, HBV-transgenic mice are the most widely used model. These mice have the viral genome integrated into the chromosome and produce infectious HBV particles or viral antigens in the liver; however, the main limitation of HBV-transgenic mouse models is that they are immunologically tolerant to viral antigens (4, 5). Various routes have been exploited to introduce the HBV genome into the hepatocytes of adult mice. One is to introduce a replication-competent HBV genome into the mouse liver by hydrodynamic injection (HDI) through the tail vein (6); although HBV replicates in the mouse liver, the virus is rapidly cleared by immune responses against HBV proteins (7). Recently, Huang and colleagues used HDI to create a nontransgenic model of persistent HBV replication (8). The virus persisted in 40% of mice or was eliminated according to the genetic background. These mice rapidly develop anti-hepatitis B virus core (HBc) antibody, which is the first serological marker of acute HBV infection in humans. An alternative method uses adenoviral vectors to transfer 1.3 copies of the HBV genome into immunocompetent mice (9, 10), and acute or chronic HBV infection was obtained depending on the dose of adenoviral vector injected.Here, we describe an alternative murine model for the study of HBV persistence based on the liver-targeted transduction of adeno-associated virus serotype 2/8 (AAV2/8). We produced an AAV2/8 construct carrying a replication-competent HBV DNA genome and by intravenous injection established a model of HBV persistence in humanized HLA-A2/DR1 immunocompetent mice. Hepatitis B virus surface antigen (HBsAg), hepatitis B virus e antigen (HBeAg), and HBV DNA persisted for at least 1 year in sera of all AAV2/8-injected mice, and viral replication intermediates and transcripts were detected in their livers. HBcAg was expressed in 60% of hepatocytes without significant inflammation in the liver. The persistence of infection was associated with the presence of regulatory T cells (Tregs) in the liver. This mouse model of HBV persistence recapitulates viral and histological characteristics of human chronic HBV infection in the immunetolerant stage of the disease (11,12).In HLA-A2/DR1 mice, cellular immune responses were completely restricted to HLA molecules. Antibody, T-helper, and cytotoxic-T-lymphocyte responses to vaccination with recombinant HBsAg or HBsAg-expressing DNA were similar to those in vaccinated humans (13,14) or in HBV-infected individuals (15). Therefore, this AAV2/8-HBV-transduced HLA-A2/DR1 murine model may be useful fo...

show abstract

Section: Discussionmentioning

confidence: 56%

Adeno-Associated Virus-Mediated Gene Transfer Leads to Persistent Hepatitis B Virus Replication in Mice Expressing HLA-A2 and HLA-DR1 Molecules

Dion

Bourgine

Godon

et al. 2013

J Virol

100

125

View full text Add to dashboard Cite

show abstract

“…1,19 This phase is more frequent and prolonged in subjects infected perinatally and is associated with preserved HBV specific T cell function at least until young adulthood. 20 The rate of spontaneous HBeAg loss is very low in this phase. These patients are highly contagious due to the high levels of HBV DNA.…”

Section: Natural History and New Nomenclature For The Chronic Statesmentioning

confidence: 90%

EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection

Lampertico¹,

Agarwal²,

Berg³

et al. 2017

Journal of Hepatology

3,846

3,081

View full text Add to dashboard Cite

“…Finally, we determined whether cross-presentation of in vivo-captured antigen by moDCs could be used to expand autologous HBV-specific T cells in chronic HBV patients. HBV-specific T cells are functionally and numerically impaired in chronic HBV patients (19), but can still be detected in low numbers in young adults (20), patients under anti-viral therapy (21), or those with low HBV-DNA (22). We tested 20 patients (Supplemental Table 6), 16 under antiviral therapy and an additional 4 that were treatment naive (CHB-29-32).…”

Section: Cross-presentation Of In Vivo-captured Hbsag By Mn-derived Dmentioning

confidence: 99%

“…After years of exposure to high levels of viral antigen, T cells either display an exhausted phenotype (23,24,41,42) or are deleted (22,43). However, recent data has shown that younger patients (<30 years) still possess HBV-specific T cells (20) and long-term antiviral therapy can, at least partially, restore HBV-specific T cells in adults (21). Therefore, applying this approach in patients under successful antiviral therapy would likely be the best route to expanding endogenous T cells using circulating antigen captured by CD14 MNs.…”

Section: Figurementioning

confidence: 99%

Mobilizing monocytes to cross-present circulating viral antigen in chronic infection

Gehring

Haniffa²,

Kennedy³

et al. 2013

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

Selection of antigens for therapeutic vaccination against chronic viral infections is complicated by pathogen genetic variations. We tested whether antigens present during persistent viral infections could provide a personalized antigenic reservoir for therapeutic T cell expansion in humans. We focused our study on the HBV surface antigen (HBsAg), which is present in microgram quantities in the serum of chronic HBV patients. We demonstrated by quantitative fluorescent microscopy that, out of 6 professional APC populations in the circulation, only CD14 monocytes (MNs) retained an HBsAg depot. Using TCR-redirected CD8 + T cells specific for MHC-I-restricted HBV epitopes, we showed that, despite being constantly exposed to antigen, ex vivoisolated APCs did not constitutively activate HBV-specific CD8 + T cells. However, differentiation of HBsAg + CD14 MNs from chronic patients to MN-derived DCs (moDCs) induced cross-presentation of the intracellular reservoir of viral antigen. We exploited this mechanism to cross-present circulating viral antigen and showed that moDCs from chronically infected patients stimulated expansion of autologous HBV-specific T cells. Thus, these data demonstrate that circulating viral antigen produced during chronic infection can serve as a personalized antigenic reservoir to activate virus-specific T cells. IntroductionTherapeutic vaccination for chronic infections, be it recombinant antigens, peptides, viral vectors, DNA, or DCs, are hindered by the need to select appropriate antigens. It is a major complicating factor due to the evolutionary diversity that pathogens have developed in response to selective forces exerted by individual (immune response) or environmental (drugs, vectors) factors. Moreover, peptides covering conserved regions for vaccination are HLA restricted and can only be applied to selected patients with the appropriate HLA. As a result, recombinant antigens or DNA vectors coding pathogen proteins may misdirect the intended immune response due to differences between the infectious pathogen and the antigen sequence utilized for vaccination.A hallmark of many chronic infections is the constant production of pathogen proteins. This is particularly evident in HBV infection, where viral titers can reach 10 9 -10 10 virions/ml in the serum. The HBV surface antigen (HBsAg) is produced in excess of whole virions and reaches concentrations well into the μg/ml range (1). While persistently present viral antigen is generally considered a negative factor (2), the abundance of endogenously produced viral antigen could be internalized by different cell types. Proper activation of cells internalizing antigen in the circulation of chronic patients could provide a target for therapeutic vaccination and stimulate T cells with antigen customized to the patient's viral genome.HBV does not infect or productively replicate in human PBMCs (3), and systematic analysis of cells capable of internalizing circu-

show abstract

Preserved T-Cell Function in Children and Young Adults With Immune-Tolerant Chronic Hepatitis B

Cited by 262 publications

References 26 publications

Adeno-Associated Virus-Mediated Gene Transfer Leads to Persistent Hepatitis B Virus Replication in Mice Expressing HLA-A2 and HLA-DR1 Molecules

Adeno-Associated Virus-Mediated Gene Transfer Leads to Persistent Hepatitis B Virus Replication in Mice Expressing HLA-A2 and HLA-DR1 Molecules

EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection

Mobilizing monocytes to cross-present circulating viral antigen in chronic infection

Contact Info

Product

Resources

About