Direct ex vivo analysis of hepatitis B virus-specific CD8+ T cells associated with the control of infection

Maini, Mala K.; Boni, Carolina; Ogg, Graham S.; King, Abigail Selzer; Reignat, Stephanie; Lee, Chun Kyon; Larrubia, J.R.; Webster, George; McMichael, Andrew J.; Ferrari, Carlo; Williams, Roger; Vergani, Diego; Bertoletti, Antonio

doi:10.1016/s0016-5085(99)70289-1

Cited by 341 publications

(272 citation statements)

References 34 publications

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“…This confirms the relevance of the low responses against weak epitopes that could also be due to the limited number of CD8 ϩ T cells in these Tg mice that never exceeded 5%. Moreover, in humans only CD8 ϩ T cells specific for dominant epitopes (HBs 335-343 or HBc 18 -27 ) have been detected ex vivo by tetramer staining without amplification (45). In contrast, detection of cytotoxic activity specific for less dominant epitopes required in vitro stimulation of T cells during at least 2 wk and in the presence of cytokines (24).…”

Section: Discussionmentioning

confidence: 99%

“…During acute HBV infection in humans the cytotoxic response is strong, polyclonal, and multiepitopic and is associated with viral clearance (46,47). In self-limited acute infection several epitopes, notably HBc 18 -27 , HBs [183][184][185][186][187][188][189][190][191] , and HBs 335-343 , are recognized by the majority of infected patients (4,45). The frequency of HBV-specific CD8 ϩ T cells detected by tetramer staining in acutely infected patients varied from 0.4 to 1.2/1000 CD8 ϩ T cells depending on the epitope and the patient (45).…”

Section: Discussionmentioning

confidence: 99%

“…In self-limited acute infection several epitopes, notably HBc 18 -27 , HBs [183][184][185][186][187][188][189][190][191] , and HBs 335-343 , are recognized by the majority of infected patients (4,45). The frequency of HBV-specific CD8 ϩ T cells detected by tetramer staining in acutely infected patients varied from 0.4 to 1.2/1000 CD8 ϩ T cells depending on the epitope and the patient (45). In addition, in uninfected but intradermally HBsAg-vaccinated individuals, CD8 ϩ T cell responses were measured by ex vivo ELISPOT assay, with frequencies for HLA-A2-restricted envelope epitopes ranging from 0.3 to 1.2/1000 CD8 ϩ T cells (48).…”

Section: Discussionmentioning

confidence: 99%

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Multiepitopic HLA-A*0201-Restricted Immune Response Against Hepatitis B Surface Antigen After DNA-Based Immunization

Loirat

Lemonnier

Michel

2000

The Journal of Immunology

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CTL together with anti-envelope Abs represent major effectors for viral clearance during hepatitis B virus (HBV) infection. The induction of strong cytotoxic and Ab responses against the envelope proteins after DNA-based immunization has been proposed as a promising therapeutic approach to mediate viral clearance in chronically infected patients. Here, we studied the CTL responses against previously described hepatitis B surface Ag (HBsAg)-HLA-A*0201-restricted epitopes after DNA-based immunization in HLA-A*0201 transgenic mice. The animal model used was Human Human Db (HHD) mice, which are deficient for mouse MHC class I molecules (β2-microglobulin−/− Db−/−) and transgenic for a chimeric HLA-A*0201/Db molecule covalently bound to the human β2-microglobulin (HHD+/+). Immunization of these mice with a DNA vector encoding the small and the middle HBV envelope proteins carrying HBsAg induced CTL responses against several epitopes in each animal. This study performed on a large number of animals described dominant epitopes with specific CTL induced in all animals and others with a weaker frequency of recognition. These results confirmed the relevance of the HHD transgenic mouse model in the assessment of vaccine constructs for human use. Moreover, genetic immunization of HLA-A2 transgenic mice generates IFN-γ-secreting CD8+ T lymphocytes specific for endogenously processed peptides and with recognition specificities similar to those described during self-limited infection in humans. This suggests that responses induced by DNA immunization could have the same immune potential as those developing during natural HBV infection in human patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Multiepitopic HLA-A*0201-Restricted Immune Response Against Hepatitis B Surface Antigen After DNA-Based Immunization

Loirat

Lemonnier

Michel

2000

The Journal of Immunology

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“…1 Thus, control of HBV infection is associated with a multispecific and polyclonal cytotoxic T-cell response and a strong type 1 T helper cell response. 2,3 In contrast, chronically infected patients display oligoclonal T helper cell responses with weak or undetectable cytotoxic T-cell activity. 4 Dendritic cells (DC) are the most important professional antigen-presenting cells.…”

Section: H Epatitis B Virus (Hbv) Infection Represents Amentioning

confidence: 99%

Dendritic cells take up viral antigens but do not support the early steps of hepatitis B virus infection

et al. 2006

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Dendritic cells (DC) of hepatitis B virus (HBV) carriers have been reported to exhibit functional impairment. Possible explanations for this phenomenon are infection of HBV by DC or alteration of DC function by HBV. We therefore analyzed whether DC support the different steps of HBV infection and replication: uptake, deposition of the HBV genome in the nucleus, antigen expression, and progeny virus release. When HBV genomes were artificially introduced into monocyte-derived DC by adenoviral vectors, low-level expression of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) but no HBV replication was detected. When monocyte-derived DC were subjected to wild-type HBV or a recombinant HBV expressing Renilla luciferase under a non-liver-specific promoter, intracellular HBV DNA was detected in a low percentage of cells. However, neither nuclear cccDNA was formed nor luciferase activity was detected, indicating that either uncoating or nucleocytoplasmic transport were blocked. To verify our observation in the in vivo situation, myeloid and plasmacytoid DC were isolated from blood of high viremic HBV carriers, and analyzed by quantitative polymerase chain reaction (PCR) and electron microscopy. Although circulating DC had in vivo been exposed to more than 10 4 HBV virions per cell, HBV genomic DNA was hardly detected, and no nuclear cccDNA was detected at all. By using electron microscopy, subviral particles were found in endocytic vesicles, but virions were undetectable as were viral capsids in the cytoplasm. H epatitis B virus (HBV) infection represents a major health problem worldwide. Over 350 million individuals are chronically infected with HBV and are at high risk to develop liver cirrhosis or hepatocellular carcinoma. To eliminate the virus after infection, a strong humoral and cellular immune response is required. 1 Thus, control of HBV infection is associated with a multispecific and polyclonal cytotoxic T-cell response and a strong type 1 T helper cell response. 2,3 In contrast, chronically infected patients display oligoclonal T helper cell responses with weak or undetectable cytotoxic T-cell activity. 4 Dendritic cells (DC) are the most important professional antigen-presenting cells. They act as key players in initiating virus-specific T-cell responses. 5 This is reflected by the fact that viruses can evade immune responses by impairing DC function. [6][7][8] The role of DC during HBV infection was intensively studied during the last years, but whether total numbers of DC are reduced during chronic infection is discussed controversary. [9][10][11] In some studies, functional deficits of these cells were reported on contact of moDC with HBV, 14 whereas they remained minor in others. 12 Whether the weak or absent T-cell response described in chronic hepatitis B patients results from a defect in the DC compartment, which is caused by the virus itself, is unclear. Theoretically, numbers or functionality of DC subsets could be affected by interaction of surface receptors on DC with either vi...

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“…Polyclonal and multispecific cytotoxic Tlymphocyte activity against HBV could be detected in patients with acute self-limiting HBV infection. 14,15 However, in chronically infected individuals, HBV-specific CD8 1 T cells persist in a non-functional 'exhausted' state, characterized by an inability to produce important antiviral cytokines (e.g., IFN-c and TNFa), low cytotoxic activities and low proliferation in response to cognate antigen. 16 The exhaustion of specific cytotoxic CD8 1 T-cell response mainly results from high levels of viral antigen and reduced CD4 1 T helper cells, supporting a key role for CD4 1 T helper cells in maintaining fully functional antigenspecific CD8 1 T-cell responses.…”

Section: Function Of Il-21 In Cellular Immune Responsesmentioning

confidence: 99%

Role of interleukin-21 in HBV infection: friend or foe?

Tang

Hou

2014

Cell Mol Immunol

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Direct ex vivo analysis of hepatitis B virus-specific CD8+ T cells associated with the control of infection

Cited by 341 publications

References 34 publications

Multiepitopic HLA-A*0201-Restricted Immune Response Against Hepatitis B Surface Antigen After DNA-Based Immunization

Multiepitopic HLA-A*0201-Restricted Immune Response Against Hepatitis B Surface Antigen After DNA-Based Immunization

Dendritic cells take up viral antigens but do not support the early steps of hepatitis B virus infection

Role of interleukin-21 in HBV infection: friend or foe?

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