The Experts below are selected from a list of 315 Experts worldwide ranked by ideXlab platform
Francis V Chisari - One of the best experts on this subject based on the ideXlab platform.
-
cd8 t cells mediate viral clearance and disease pathogenesis during <B>AcuteB> <B>HepatitisB> B virus infection
Journal of Virology, 2003Co-Authors: Robert Thimme, Robert H Purcell, Stefan Wieland, Carola Steiger, John Ghrayeb, Keith A Reimann, Francis V ChisariAbstract:Although the CD4 + - and CD8 + -T-cell responses to the <B>HepatitisB> B virus (HBV) are thought to Be crucial for the control of HBV infection, the relative contriBution of each T-cell suBset as an effector of viral clearance is not known. To examine this question, we monitored the course of HBV infection in control, CD4-depleted, and CD8-depleted chimpanzees. Our results demonstrate that CD8 + cells are the main effector cells responsiBle for viral clearance and disease pathogenesis during <B>AcuteB> HBV infection, and they suggest that viral clearance is mediated By Both noncytolytic and cytolytic effector functions of the CD8 + -T-cell response.
-
hydrodynamic injection of viral dna a mouse model of <B>AcuteB> <B>HepatitisB> B virus infection
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Priscilla L Yang, Alana Althage, Josan Chung, Francis V ChisariAbstract:<B>HepatitisB> B virus (HBV) is a prototype for liver-specific pathogens in which the failure of the immune system to mount an effective response leads to chronic infection. Our understanding of the immune response to HBV is incomplete, largely due to the narrow host restriction of this pathogen and the limitations of existing experimental models. We have developed a murine model for studying human HBV replication, immunogenicity, and control. After transfection of hepatocytes in vivo with a replication-competent, over-length, linear HBV genome, viral antigens and replicative intermediates were synthesized and virus was secreted into the Blood. Viral antigens disappeared from the Blood as early as 7 days after transfection, coincident with the appearance of antiviral antiBodies. HBV transcripts and replicative intermediates disappeared from the liver By day 15, after the appearance of antiviral CD8 + T cells. In contrast, the virus persisted for at least 81 days after transfection of NOD/Scid mice, which lack functional T cells, B cells, and natural killer (NK) cells. Thus, the outcome of hydrodynamic transfection of HBV depends on the host immune response, as it is during a natural infection. The methods we descriBe will allow the examination of viral dynamics in a tightly controlled in vivo system, the application of mutagenesis methods to the study of the HBV life cycle in vivo, and the dissection of the immune response to HBV using genetically modified mice whose immunoregulatory and immune effector functions have Been deleted or overexpressed. In addition, this methodology represents a prototype for the study of other known and to-Be-discovered liver-specific pathogens.
-
human histocompatiBility leukocyte antigen Binding supermotifs predict Broadly cross reactive cytotoxic t lymphocyte responses in patients with <B>AcuteB> <B>HepatitisB>
Journal of Clinical Investigation, 1997Co-Authors: R Bertoni, Francis V Chisari, P Fowler, J Sidney, R W Chesnut, Alessandro SetteAbstract:The present study was designed to determine if highly conserved <B>HepatitisB> B virus (HBV)-derived peptides that Bind multiple HLA class I alleles with high affinity are recognized as cytotoxic T lymphocyte (CTL) epitopes in <B>AcuteB>ly infected patients. Peripheral Blood mononuclear cells from 67 patients with <B>AcuteB> <B>HepatitisB> B, and 12 patients convalescent from <B>AcuteB> <B>HepatitisB> B, were stimulated with three panels of peptides, each of which Bind with high affinity to several class I alleles from the HLA-A2-, HLA-A3-, or HLA-B7-supertypes. In these patients, 8 of the 19 peptides tested were found to represent CTL epitopes recognized By two or more alleles in each supertype. Two sets of nested peptides were recognized in the context of alleles with completely unrelated peptide Binding specificities. Finally, promiscuous recognition By the same CTL of a given peptide presented By target cells expressing different A2 suBtypes was also commonly oBserved. In conclusion, several HBV-specific CTL epitopes, recognized By <B>AcuteB>ly infected or convalescent patients in the context of a wide range of HLA alleles have Been identified. These results demonstrate the functional relevance of the supertype grouping of HLA class I molecules in a human viral disease setting. Furthermore, they represent a significant advance in the development of a totally synthetic vaccine to terminate chronic HBV infection and support the feasiBility of a systematic approach to development of similar vaccines for prevention and treatment of other chronic viral infections.
-
long lasting memory t cell responses following self limited <B>AcuteB> <B>HepatitisB> B
Journal of Clinical Investigation, 1996Co-Authors: Amalia Penna, Francis V Chisari, Antonio Bertoletti, Marco Artini, Albertina Cavalli, Massimo Levrero, M Pilli, Barbara Rehermann, G F Del Prete, F FiaccadoriAbstract:The molecular and cellular Basis of long-term T cell mem- ory against viral antigens is still largely undefined. To char- acterize anti-viral protection By memory T cells against non-cytopathic viruses aBle to cause <B>AcuteB> self-limited and chronic infections, such as the <B>HepatitisB> B virus (HBV), we studied HLA class II restricted responses against HBV struc- tural antigens in 17 patients with <B>AcuteB> <B>HepatitisB> B, during the <B>AcuteB> stage of infection and 2.2 to 13 yr after clinical resolu- tion of disease. Results indicate that: (a) significant T cell proliferative responses to HBV nucleocapsid antigens were detectaBle in all patients during the <B>AcuteB> phase of infection and in 14/17 also 2-13 yr after clinical resolution of disease; B) long-lasting T cell responses were sustained By CD45RO 1 T cells, predominantly expressing the phenotype of recently activated cells; c) limiting dilution analysis showed that in some patients the frequency of HBV-specific T cells was comparaBle to that oBserved in the <B>AcuteB> stage of infection and, usually, higher than in patients with chronic HBV in- fection; d) the same amino acid sequences were recognized By T cells in the <B>AcuteB> and recovery phases of infection; and e) HBV-DNA was detectaBle By nested-PCR in approxi- mately half of the suBjects. In conclusion, our results show that vigorous anti-viral T cell responses are detectaBle in vitro several years after clin- ical recovery from <B>AcuteB> <B>HepatitisB> B. Detection of minute amounts of virus in some recovered suBjects suggests that long-term maintenance of an active anti-viral T cell re- sponse could Be important not only for protection against reinfection But also for keeping the persisting virus under tight control. ( J. Clin. Invest. 1996. 98:1185-1194.) Key words: viremiacytokinestetanustoxoidHBV nucleo- capsid antigensHBV envelope antigens
-
<B>HepatitisB> B virus persistence after recovery from <B>AcuteB> viral <B>HepatitisB>
Journal of Clinical Investigation, 1994Co-Authors: Tomasz I Michalak, Claudio Pasquinelli, Stephane Guilhot, Francis V ChisariAbstract:Contrary to current opinion, the disappearance of <B>HepatitisB> B surface antigen (HBsAg) from the serum, the development of anti-HBs antiBodies, and normalization of liver function may not reflect complete virological recovery from <B>AcuteB> <B>HepatitisB> B virus (HBV) infection. By using the polymerase chain reaction (PCR), in the current study we demonstrate long-term persistence of HBV DNA in the serum and peripheral Blood mononuclear cells (PBMC) of four patients for up to 70 mo after complete clinical, Biochemical, and serological recovery from <B>AcuteB> viral <B>HepatitisB>. Serum HBV DNA reactivity co-sedimented with HBsAg in sucrose gradients, and it displayed the size and density characteristics of naked core particles and intact HBV virions, presumaBly contained within circulating immune complexes in these anti-HBs antiBody-positive sera. HBV DNA was also present in PBMC in late convalescent samples from all four patients, and HBV RNA was detected in late convalescent phase PBMC in two of these patients. These results suggest that HBV DNA, and possiBly HBV virions, can Be present in the serum, and that the viral genome can persist in a transcriptionally active form in PBMC for > 5 yr after complete clinical and serological recovery from <B>AcuteB> viral <B>HepatitisB>.
Antonio Bertoletti - One of the best experts on this subject based on the ideXlab platform.
-
increased levels of arginase in patients with <B>AcuteB> <B>HepatitisB> B suppress antiviral t cells
Gastroenterology, 2012Co-Authors: Elena Sandalova, Antonio Bertoletti, Diletta Laccabue, Carolina Boni, Tsunamasa Watanabe, Anthony T Tan, Ho Zi Zong, Carlo FerrariAbstract:Background & Aims During viral infection, the activities of virus-specific CD8 + T cells are carefully regulated to prevent severe damage of the infected organs. We investigated the mechanisms that control the functions of activated T cells. Methods We measured the size of the population of activated and proliferating CD8 + T cells and the functional pattern of CD8 + T cells specific for the entire <B>HepatitisB> B virus proteome and for selected heterologous virus (Epstein–Barr virus, human cytomegalovirus, and influenza virus) using Blood samples from 18 patients with <B>AcuteB> <B>HepatitisB> B. We analyzed the effects of different modulatory mechanisms, such as inhiBitory molecules, suppressive cytokines (interleukin-10), and arginase, on the activities of CD8 + T cells. Results In patients with <B>AcuteB> <B>HepatitisB> B, the expansion of activated and proliferating (HLA-DR/CD38 + , Ki-67 + /Bcl-2 low ) CD8 + T cells did not quantitatively match their specific functions ex vivo; virus-specific CD8 + T cells had functional impairments that were temporally restricted to the <B>AcuteB> phase of viral <B>HepatitisB>. These impairments in function were not limited to HBV-specific CD8 + T cells But were also oBserved in CD8 + T cells with specificities for other viruses. We investigated possiBle causes of antigen-independent CD8 + T cell inhiBition and found that the increased levels of arginase oBserved in patients with <B>AcuteB> <B>HepatitisB> could suppress the function of activated, But not resting, CD8 + T cells. Conclusions The increased level of arginase in patients with <B>AcuteB> <B>HepatitisB> B suppresses the functions of activated CD8 + T cells. This mechanism might limit the amount of liver damage caused By activated CD8 + T cells in patients with <B>AcuteB> HBV infection.
-
long lasting memory t cell responses following self limited <B>AcuteB> <B>HepatitisB> B
Journal of Clinical Investigation, 1996Co-Authors: Amalia Penna, Francis V Chisari, Antonio Bertoletti, Marco Artini, Albertina Cavalli, Massimo Levrero, M Pilli, Barbara Rehermann, G F Del Prete, F FiaccadoriAbstract:The molecular and cellular Basis of long-term T cell mem- ory against viral antigens is still largely undefined. To char- acterize anti-viral protection By memory T cells against non-cytopathic viruses aBle to cause <B>AcuteB> self-limited and chronic infections, such as the <B>HepatitisB> B virus (HBV), we studied HLA class II restricted responses against HBV struc- tural antigens in 17 patients with <B>AcuteB> <B>HepatitisB> B, during the <B>AcuteB> stage of infection and 2.2 to 13 yr after clinical resolu- tion of disease. Results indicate that: (a) significant T cell proliferative responses to HBV nucleocapsid antigens were detectaBle in all patients during the <B>AcuteB> phase of infection and in 14/17 also 2-13 yr after clinical resolution of disease; B) long-lasting T cell responses were sustained By CD45RO 1 T cells, predominantly expressing the phenotype of recently activated cells; c) limiting dilution analysis showed that in some patients the frequency of HBV-specific T cells was comparaBle to that oBserved in the <B>AcuteB> stage of infection and, usually, higher than in patients with chronic HBV in- fection; d) the same amino acid sequences were recognized By T cells in the <B>AcuteB> and recovery phases of infection; and e) HBV-DNA was detectaBle By nested-PCR in approxi- mately half of the suBjects. In conclusion, our results show that vigorous anti-viral T cell responses are detectaBle in vitro several years after clin- ical recovery from <B>AcuteB> <B>HepatitisB> B. Detection of minute amounts of virus in some recovered suBjects suggests that long-term maintenance of an active anti-viral T cell re- sponse could Be important not only for protection against reinfection But also for keeping the persisting virus under tight control. ( J. Clin. Invest. 1996. 98:1185-1194.) Key words: viremiacytokinestetanustoxoidHBV nucleo- capsid antigensHBV envelope antigens
-
Definition of a minimal optimal cytotoxic T-cell epitope within the <B>HepatitisB> B virus nucleocapsid protein.
Journal of Virology, 1993Co-Authors: Antonio Bertoletti, Francis V Chisari, Amalia Penna, S Guilhot, L. Galati, Gabriele Missale, P Fowler, H J Schlicht, A Vitiello, Robert Cardiff-by-the-sea ChesnutAbstract:Residues 11 to 27 of the <B>HepatitisB> B virus nucleocapsid antigen contain a cytotoxic T-cell epitope that is recognized By cytotoxic T cells from virtually all HLA-A2-positive patients with <B>AcuteB> <B>HepatitisB> B virus infection. Using panels of truncated and overlapping peptides, we now show that the optimal amino acid sequence recognized By cytotoxic T cells is a 10-mer (residues 18 to 27) containing the predicted peptide-Binding motif for HLA-A2 and that this peptide can stimulate cytotoxic T cells aBle to recognize endogenously synthesized <B>HepatitisB> B core antigen. Since patients with chronic <B>HepatitisB> B virus infection fail to mount an efficient cytotoxic T-cell response to it, this epitope might serve as the starting point for the design of synthetic peptide-Based immunotherapeutic strategies to terminate persistent viral infection.
-
cytotoxic t lymphocytes recognize an hla a2 restricted epitope within the <B>HepatitisB> B virus nucleocapsid antigen
Journal of Experimental Medicine, 1991Co-Authors: Amalia Penna, Francis V Chisari, Antonio Bertoletti, Gabriele Missale, P Fowler, F Fiaccadori, T Giuberti, Carlo FerrariAbstract:The aBsence of readily manipulaBle experimental systems to study the cytotoxic T lymphocyte (CTL) response against <B>HepatitisB> B virus (HBV) antigens has thus far precluded a definitive demonstration of the role played By this response in the pathogenesis of liver cell injury and viral clearance during HBV infection. To circumvent the proBlem that HBV infection of human cells in vitro for production of stimulator/target systems for CTL analysis is not feasiBle, a panel of 22 overlapping synthetic peptides covering the entire amino acid sequence of the HBV core (HBcAg) and e (HBeAg) antigens were used to induce and to analyze the HBV nucleocapsid-specific CTL response in nine patients with <B>AcuteB> <B>HepatitisB> B, six patients with chronic active <B>HepatitisB> B, and eight normal controls. By using this approach, we have identified an HLA-A2-restricted CTL epitope, located within the NH2-terminal region of the HBV core molecule, which is shared with the e antigen and is readily recognized By peripheral Blood mononuclear cells from patients with self-limited <B>AcuteB> <B>HepatitisB> B But less efficiently in chronic HBV infection. Our study provides the first direct evidence of HLA class I-restricted T cell cytotoxicity against HBV in humans. Furthermore, the different response in HBV-infected suBjects who successfully clear the virus (<B>AcuteB> patients) in comparison with patients who do not succeed (chronic patients) suggests a pathogenetic role for this CTL activity in the clearance of HBV infection.
Alan S Perelson - One of the best experts on this subject based on the ideXlab platform.
-
<B>AcuteB> <B>HepatitisB> B virus infection in humanized chimeric mice has multiphasic viral kinetics
Hepatology, 2018Co-Authors: Yuji Ishida, Alan S Perelson, Tje Lin Chung, Michio Imamura, Nobuhiko Hiraga, Suranjana Sen, Hiroshi Yokomichi, Chise Tateno, Laetitia Canini, Susan L UprichardAbstract:Chimeric urokinase type plasminogen activator (uPA)/severely severe comBined immunodeficiency (SCID) mice reconstituted with humanized livers are useful for studying <B>HepatitisB> B virus (HBV) infection in the aBsence of an adaptive immune response. However, the detailed characterization of HBV infection kinetics necessary to enaBle in-depth mechanistic studies in this in vivo HBV infection model is lacking. To characterize HBV kinetics post-inoculation (p.i.) to steady state, 42 mice were inoculated with HBV. Serum HBV DNA was frequently measured from 1 minute to 63 days p.i. Total intrahepatic HBV DNA, HBV covalently closed circular DNA (cccDNA), and HBV RNA was measured in a suBset of mice at 2, 4, 6, 10, and 13 weeks p.i. HBV half-life (t1/2 ) was estimated using a linear mixed-effects model. During the first 6 hours p.i., serum HBV declined in repopulated uPA/SCID mice with a t1/2 = 62 minutes (95% confidence interval [CI] = 59-67). Thereafter, viral decline slowed followed By a 2-day lower plateau. SuBsequent viral amplification was multiphasic with an initial mean douBling time of t2 = 8 ± 3 hours followed By an interim plateau Before prolonged amplification (t2 = 2 ± 0.5 days) to a final HBV steady state of 9.3 ± 0.3 log copies (cps)/mL. Serum HBV and intrahepatic HBV DNA were positively correlated (R2 = 0.98). Conclusion HBV infection in uPA/SCID chimeric mice is highly dynamic despite the aBsence of an adaptive immune response. Serum HBV t1/2 in humanized uPA/SCID mice was estimated to Be ∼1 hour regardless of inoculum size. The HBV <B>AcuteB> infection kinetics presented here is an important step in characterizing this experimental model system so that it can Be effectively used to elucidate the dynamics of the HBV life cycle and thus possiBly reveal effective antiviral drug targets. (Hepatology 2018).
-
modeling the mechanisms of <B>AcuteB> <B>HepatitisB> B virus infection
Journal of Theoretical Biology, 2007Co-Authors: Stanca M Ciupe, Ruy M Ribeiro, Patrick W Nelson, Alan S PerelsonAbstract:Mathematical models have Been used to understand the factors that govern infectious disease progression in viral infections. Here we focus on <B>HepatitisB> B virus (HBV) dynamics during the <B>AcuteB> stages of the infection and analyze the immune mechanisms responsiBle for viral clearance. We start By presenting the Basic model used to interpret HBV therapy studies conducted in chronically infected patients. We then introduce additional models to study <B>AcuteB> infection where immune responses presumaBly play an important role in determining whether the infection will Be cleared or Become chronic. We add complexity incrementally and explain each step of the modeling process. Finally, we validate the model against experimental data to determine how well it represents the Biological system and, consequently, how useful are its predictions. In particular, we find that a cell-mediated immune response plays an important role in controlling the virus after the peak in viral load.
-
the role of cells refractory to productive infection in <B>AcuteB> <B>HepatitisB> B viral dynamics
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Stanca M Ciupe, Ruy M Ribeiro, Patrick W Nelson, Geoffrey Dusheiko, Alan S PerelsonAbstract:During <B>AcuteB> <B>HepatitisB> B virus (HBV) infection viral loads reach high levels (≈1010 HBV DNA per ml), and nearly every hepatocyte Becomes infected. Nonetheless, ≈85–95% of infected adults clear the infection. Although the immune response has Been implicated in mediating clearance, the precise mechanisms remain to Be elucidated. As infection clears, infected cells are replaced By uninfected ones. During much of this process the virus remains plentiful But nonetheless does not rekindle infection. Here, we analyze data from a set of individuals identified during <B>AcuteB> HBV infection and develop mathematical models to test the role of immune responses in various stages of early HBV infection. Fitting the models to data we are aBle to separate the kinetics of the noncytolytic and the cytolytic immune responses, thus explaining the relative contriBution of these two processes. We further show that we need to hypothesize that newly generated uninfected cells are refractory to productive infection. Without this assumption, viral resurgence is oBserved as uninfected cells are regenerated. Such protection, possiBly mediated By cytokines, may also Be important in resolving other <B>AcuteB> viral infections.
-
kinetics of <B>AcuteB> <B>HepatitisB> B virus infection in humans
Journal of Experimental Medicine, 2001Co-Authors: S A Whalley, Geoffrey Dusheiko, George Webster, John M Murray, D Brown, Vincent C Emery, Alan S PerelsonAbstract:Using patient data from a unique single source outBreak of <B>HepatitisB> B virus (HBV) infection, we have characterized the kinetics of <B>AcuteB> HBV infection By monitoring viral turnover in the serum during the late incuBation and clinical phases of the disease in humans. HBV replicates rapidly with minimally estimated douBling times ranging Between 2.2 and 5.8 d (mean 3.7 ± 1.5 d). After a peak viral load in serum of nearly 1010 HBV DNA copies/ml is attained, clearance of HBV DNA follows a two or three phase decay pattern with an initial rapid decline characterized By mean half-life (t1/2) of 3.7 ± 1.2 d, similar to the t1/2 oBserved in the noncytolytic clearance of covalently closed circular DNA for other hepadnaviruses. The final phase of virion clearance occurs at a variaBle rate (t1/2 of 4.8 to 284 d) and may relate to the rate of loss of infected hepatocytes. Free virus has a mean t1/2 of at most 1.2 ± 0.6 d. We estimate a peak HBV production rate of at least 1013 virions/day and a maximum production rate of an infected hepatocyte of 200–1,000 virions/day, on average. At this peak rate of virion production we estimate that every possiBle single and most douBle mutations would Be created each day.
Carlo Ferrari - One of the best experts on this subject based on the ideXlab platform.
-
increased levels of arginase in patients with <B>AcuteB> <B>HepatitisB> B suppress antiviral t cells
Gastroenterology, 2012Co-Authors: Elena Sandalova, Antonio Bertoletti, Diletta Laccabue, Carolina Boni, Tsunamasa Watanabe, Anthony T Tan, Ho Zi Zong, Carlo FerrariAbstract:Background & Aims During viral infection, the activities of virus-specific CD8 + T cells are carefully regulated to prevent severe damage of the infected organs. We investigated the mechanisms that control the functions of activated T cells. Methods We measured the size of the population of activated and proliferating CD8 + T cells and the functional pattern of CD8 + T cells specific for the entire <B>HepatitisB> B virus proteome and for selected heterologous virus (Epstein–Barr virus, human cytomegalovirus, and influenza virus) using Blood samples from 18 patients with <B>AcuteB> <B>HepatitisB> B. We analyzed the effects of different modulatory mechanisms, such as inhiBitory molecules, suppressive cytokines (interleukin-10), and arginase, on the activities of CD8 + T cells. Results In patients with <B>AcuteB> <B>HepatitisB> B, the expansion of activated and proliferating (HLA-DR/CD38 + , Ki-67 + /Bcl-2 low ) CD8 + T cells did not quantitatively match their specific functions ex vivo; virus-specific CD8 + T cells had functional impairments that were temporally restricted to the <B>AcuteB> phase of viral <B>HepatitisB>. These impairments in function were not limited to HBV-specific CD8 + T cells But were also oBserved in CD8 + T cells with specificities for other viruses. We investigated possiBle causes of antigen-independent CD8 + T cell inhiBition and found that the increased levels of arginase oBserved in patients with <B>AcuteB> <B>HepatitisB> could suppress the function of activated, But not resting, CD8 + T cells. Conclusions The increased level of arginase in patients with <B>AcuteB> <B>HepatitisB> B suppresses the functions of activated CD8 + T cells. This mechanism might limit the amount of liver damage caused By activated CD8 + T cells in patients with <B>AcuteB> HBV infection.
-
virus specific cd8 lymphocytes share the same effector memory phenotype But exhiBit functional differences in <B>AcuteB> <B>HepatitisB> B and c
Journal of Virology, 2002Co-Authors: Simona Urbani, Gabriele Missale, Carolina Boni, Gianfranco Elia, Cristina Cavallo, Marco Massari, Giovanni Raimondo, Carlo FerrariAbstract:<B>HepatitisB> B and <B>HepatitisB> C viruses (HBV and HCV) are Both noncytopathic and can cause <B>AcuteB> and chronic infections of the liver. Although they share tropism for the same organ, development of chronic <B>HepatitisB> is much more frequent following HCV infection, suggesting different mechanisms of viral persistence. In this study, we show that circulating HBV- and HCV-specific tetramer-positive CD8 cells during the <B>AcuteB> phase of <B>HepatitisB> B and C Belong almost entirely to an effector-memory suBset (CCR7(-) CD45RA(-)). Despite this phenotypic similarity, HBV- and HCV-specific CD8 cells show striking functional differences. HBV-specific tetramer-positive CD8 cells express high perforin content ex vivo, expand vigorously, and display efficient cytotoxic activity and gamma interferon (IFN-gamma) production upon peptide stimulation. A comparaBle degree of functional efficiency is maintained after the resolution of <B>HepatitisB> B. In contrast, HCV-specific CD8 cells in the <B>AcuteB> phase of <B>HepatitisB> C express significantly lower levels of perforin molecules ex vivo and show depressed CD8 function in terms of proliferation, lytic activity, and IFN-gamma production, irrespective of the final outcome of the disease. This defect is transient, Because HCV-specific CD8 cells can progressively improve their function in patients with self-limited <B>HepatitisB> C, while the CD8 function remains persistently depressed in suBjects with a chronic evolution.
-
cytotoxic t lymphocytes recognize an hla a2 restricted epitope within the <B>HepatitisB> B virus nucleocapsid antigen
Journal of Experimental Medicine, 1991Co-Authors: Amalia Penna, Francis V Chisari, Antonio Bertoletti, Gabriele Missale, P Fowler, F Fiaccadori, T Giuberti, Carlo FerrariAbstract:The aBsence of readily manipulaBle experimental systems to study the cytotoxic T lymphocyte (CTL) response against <B>HepatitisB> B virus (HBV) antigens has thus far precluded a definitive demonstration of the role played By this response in the pathogenesis of liver cell injury and viral clearance during HBV infection. To circumvent the proBlem that HBV infection of human cells in vitro for production of stimulator/target systems for CTL analysis is not feasiBle, a panel of 22 overlapping synthetic peptides covering the entire amino acid sequence of the HBV core (HBcAg) and e (HBeAg) antigens were used to induce and to analyze the HBV nucleocapsid-specific CTL response in nine patients with <B>AcuteB> <B>HepatitisB> B, six patients with chronic active <B>HepatitisB> B, and eight normal controls. By using this approach, we have identified an HLA-A2-restricted CTL epitope, located within the NH2-terminal region of the HBV core molecule, which is shared with the e antigen and is readily recognized By peripheral Blood mononuclear cells from patients with self-limited <B>AcuteB> <B>HepatitisB> B But less efficiently in chronic HBV infection. Our study provides the first direct evidence of HLA class I-restricted T cell cytotoxicity against HBV in humans. Furthermore, the different response in HBV-infected suBjects who successfully clear the virus (<B>AcuteB> patients) in comparison with patients who do not succeed (chronic patients) suggests a pathogenetic role for this CTL activity in the clearance of HBV infection.
Hiroshi Yotsuyanagi - One of the best experts on this subject based on the ideXlab platform.
-
risk factors for long term persistence of serum <B>HepatitisB> B surface antigen following <B>AcuteB> <B>HepatitisB> B virus infection in japanese adults
Hepatology, 2014Co-Authors: Kiyoaki Ito, Hiroshi Yotsuyanagi, Hiroshi Yatsuhashi, Yoshiyasu Karino, Yasuhiro Takikawa, Takafumi Saito, Yasuji Arase, Fumio Imazeki, Masayuki Kurosaki, Takeji UmemuraAbstract:The proportion of patients who progress to chronicity following <B>AcuteB> <B>HepatitisB> B (AHB) varies widely worldwide. Moreover, the association Between viral persistence after AHB and <B>HepatitisB> B virus (HBV) genotypes in adults remains unclear. A nationwide multicenter study was conducted throughout Japan to evaluate the influence of clinical and virological factors on chronic outcomes in patients with AHB. For comparing factors Between AHB patients with viral persistence and those with self-limited infection, 212 AHB patients without human immunodeficiency virus (HIV) coinfection were oBserved in 38 liver centers until serum <B>HepatitisB> B surface antigen (HBsAg) disappeared or a minimum of 6 months in cases where HBsAg persisted. The time to disappearance of HBsAg was significantly longer for genotype A patients than that of patients infected with non-A genotypes. When chronicity was defined as the persistence of HBsAg positivity for more than 6 or 12 months, the rate of progression to chronicity was higher in patients with genotype A, although many cases caused By genotype A were prolonged cases of AHB, rather than chronic infection. Multivariate logistic regression analysis revealed only genotype A was independently associated with viral persistence following AHB. A higher peak level of HBV DNA and a lower peak of alanine aminotransferase (ALT) levels were characteristics of AHB caused By genotype A. Treatment with nucleotide analogs (NAs) did not prevent progression to chronic infection following AHB overall. SuBanalysis suggested early NA initiation may enhance the viral clearance. Conclusion: Genotype A was an independent risk factor for progression to chronic infection following AHB. Our data will Be useful in elucidating the association Between viral persistence after AHB, host genetic factors, and treatment with NAs in future studies. (Hepatology 2014;58:89–97)
-
high levels of <B>HepatitisB> B virus after the onset of disease lead to chronic infection in patients with <B>AcuteB> <B>HepatitisB> B
Clinical Infectious Diseases, 2013Co-Authors: Hiroshi Yotsuyanagi, Kiyomi Yasuda, Kyoji Moriya, Kiyoaki Ito, Norie Yamada, Hideaki Takahashi, Chiaki Okuse, Michihiro Suzuki, Masashi MizokamiAbstract:BACKGROUND Some patients with <B>AcuteB> <B>HepatitisB> B virus (HBV) infection develop chronic infection. However, the method for identifying these patients has not Been estaBlished. METHODS We followed 215 Japanese patients with <B>AcuteB> HBV infection until the clearance of <B>HepatitisB> B surface antigen (HBsAg) or the development of chronic infection. Levels of HBsAg and HBV DNA were serially monitored from the onset. RESULTS Of the 215 patients, 113 (52.5%) possessed HBV genotype A, 26 (12.0%) genotype B, and 73 (34.0%) genotype C. Twenty-one of the 215 (9.8%) developed chronic infection, with the persistence of HBsAg for >6 months. The rate of chronicity of genotype A, B, and C was 12.4%, 3.8%, and 8.2%. Of the 21 patients, only 6 (2.8%) patients, including 5 with genotype A, failed to clear HBsAg within 12 months. Levels of HBsAg at 12 weeks and HBV DNA at 4 weeks were useful for distinguishing the patients who Became chronic from those who did not (P < .001 and P < .001, respectively). Likewise, the levels of HBsAg at 12 weeks and HBV DNA at 8 weeks were useful for discriminating Between the patients who lost HBsAg within 12 months and those who did not (P < .01 and P < .05, respectively). CONCLUSIONS In <B>AcuteB> HBV infection, clearance of HBV may happen Between 6 and 12 months from the onset. Only those who fail to clear HBV within 12 months from the onset may develop chronic infection.
-
distinct geographic distriButions of <B>HepatitisB> B virus genotypes in patients with <B>AcuteB> infection in japan
Journal of Medical Virology, 2005Co-Authors: Hiroshi Yotsuyanagi, Kiyomi Yasuda, Etsuro Orito, Joji Toyoda, Chiaki Okuse, Shuhei Nishiguchi, Eiichi Tomita, Keisuke Hino, Kiwamu Okita, Shiro MurashimaAbstract:Genotypes of <B>HepatitisB> B virus (HBV) were determined in 145 patients with <B>AcuteB> <B>HepatitisB> B from various districts in Japan to estaBlish their geographic distriBution and evaluating the influence on the clinical illness and outcome. Genotypes were A in 27 (19%) patients, B in 8 (5%), C in 109 (75%) and mixed with B and C in the remaining one (1%). Genotype A was more frequent in metropolitan than the other areas (21/69 (30%) vs. 6/76 (8%), P < 0.001). On phylogenetic analysis, seven of the nine (78%) HBV/A isolates selected at random clustered with those from Europe and the United States, while the remaining two with those of suBgroup A' prevalent in Asia and Africa. Maximum ALT levels were lower (2069 +/- 1075 vs. 2889 +/- 1867 IU/L, P = 0.03) and Baseline HBV DNA titers were higher (5.90 +/- 1.45 vs. 5.13 +/- 1.36 log genome equivalents (LGE)/ml, P = 0.002) in patients infected with genotype A than C. <B>HepatitisB> B surface antigen persisted longer in patients infected with genotype A than C (1.95 +/- 1.09 vs. 1.28 +/- 1.42 months, P = 0.02). HBV infection Became chronic in one (4%) patient with genotype A and one (1%) with genotype C infection. Fulminant hepatic failure developed in none of the patients with genotype A, one (13%) with genotype B and five (5%) with genotype C. The point mutation in the precore region (A1896) or the douBle mutations in the Basic core promoter (BCP) region (T1762/A1764) were detected in none of the patients with genotype A, two (25%) with genotype B and 27 (26%) with genotype C. In conclusion, genotype A is frequent in patients with <B>AcuteB> <B>HepatitisB> B in metropolitan areas of Japan, proBaBly reflecting particular transmission routes, and associated with longer and milder clinical course than genotype C.
-
persistent viremia after recovery from self limited <B>AcuteB> <B>HepatitisB> B
Hepatology, 1998Co-Authors: Hiroshi Yotsuyanagi, Kiyomi Yasuda, Shiro Iino, Kyoji Moriya, Yoshizumi Shintani, Hajime Fujie, Takeya Tsutsumi, Satoshi Kimura, M Kazuhiko D KoikeAbstract:To define the duration of viremia in the course of <B>AcuteB> <B>HepatitisB> B, we semiquantitatively determined the levels of <B>HepatitisB> B virus (HBV) DNA in the sera, using polymerase chain reaction (PCR) coupled with Southern Blotting, of non-immunocompromised patients with self-limited <B>AcuteB> <B>HepatitisB> B. In the sera of 10 of 11 patients, HBV DNA, which was presumaBly coated with viral proteins, was detected for a long period after recovery, even at the final oBservation times, which ranged from 6 to 19 months after disease onset. To characterize the mode of HBV that was present in serum, we immunoprecipitated immune complexes in sera By the addition of anti-human immunogloBulin G (IgG) and determined the levels of HBV DNA separately in the supernatants and pellets. In the <B>AcuteB> phase of <B>HepatitisB> B, high levels of HBV DNA were detected Both in the supernatants and pellets at comparative levels. After the convalescent phase, the amount of HBV DNA in the supernatant decreased with respect to that in the pellets. It is notaBle that, in most cases, serum HBV persisted as a form of immune complex even after the seroconversion to antiBody to <B>HepatitisB> B surface antigen (anti-HBs). These data suggest that the replication of HBV may persist in some organs, most likely in the liver or peripheral Blood cells, for a long period after recovery from <B>AcuteB> <B>HepatitisB> B, and the data indicate the possiBle transmission of HBV from organ transplantation donors who exhiBit serological markers of past infection only.