Cytotoxic T lymphocyte responsiveness after resolution of chronic hepatitis B virus infection.

Rehermann, Barbara; Lau, Daryl T.Y.; Hoofnagle, J H; Chisari, Francis V.

doi:10.1172/jci118592

Cited by 289 publications

(217 citation statements)

References 30 publications

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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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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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“…41 Consider, also, that there are approximately 10 12 lymphocytes in the entire body and that the HBV-specific CTL precursor frequency at the height of the CTL response in a strongly reactive patient with acute hepatitis is rarely greater than 10 Ϫ4 ; usually it is much lower. 42 Hence, there should be no more than 10 8 HBV-specific CTL in the entire body at any point in time. Therefore, if every HBV-specific CTL in the entire body were to enter the liver at the same time (highly unlikely), and if most of the hepatocytes were infected (very common), there would be 1 specific CTL in the liver for every 1000 infected hepatocytes.…”

Section: Viral Clearance By Destruction Of Infected Cellsmentioning

confidence: 99%

“…This type of CTL response is unusual, however, during HBV infection, when the CTL response is typically vigorous and multispecific during acute hepatitis and weak or undetectable during chronic hepatitis. 42,65,66,72 Accordingly, mutational inactivation of CTL epitopes is extremely uncommon during chronic HBV infection. 73 Nonetheless, strong, narrowly focused CTL responses do occur occasionally in these patients, 20 and in this setting viral escape mutations can occur.…”

Section: Mechanisms Of Hbv Persistencementioning

confidence: 99%

Viruses, Immunity, and Cancer: Lessons from Hepatitis B

Chisari

2000

The American Journal of Pathology

281

226

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“…In acutely infected patients the immune response includes high Ab titers against the core and the envelope proteins as well as vigorous, polyclonal, and multispecific cellular responses (3). On the other hand, in patients who do not clear the viral infection or who were infected early in life and become chronic carriers, the cellular response is undetectable or weak and is restricted to few antigenic determinants (4). Several observations suggest that cytotoxic T cells are required for the viral clearance, although lysis of infected hepatocytes is unlikely to be the only mechanism through which CD8 ϩ T cells exert their anti-viral effect.…”

Section: H Epatitis B Virus (Hbv)mentioning

confidence: 99%

“…RBC-depleted splenocytes (0.83% NH 4 Cl, 5 min, on ice) were cultured (5 ϫ 10 6 cells in 24-well plates) in ␣-MEM (Life Technologies) supplemented with 10 mM HEPES, nonessential amino acids, 1 mM sodium pyruvate, 5 ϫ 10 Ϫ5 M 2-ME, antibiotics, and 10% FCS (Myoclone, Life Technologies). These cells were stimulated for 6 -7 days with peptide-loaded LPS-blast cells as APCs at an effector-presenting cell ratio of 2:1 to 1:1.…”

Section: Measurement Of Ctl Activitymentioning

confidence: 99%

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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Cytotoxic T lymphocyte responsiveness after resolution of chronic hepatitis B virus infection.

Cited by 289 publications

References 30 publications

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

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

Viruses, Immunity, and Cancer: Lessons from Hepatitis B

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

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