Hepatitis B Virus Mutants with Precore-Region Defects in Two Babies with Fulminant Hepatitis and Their Mothers Positive for Antibody to Hepatitis B e Antigen

Terazawa, Sousuke; Kojima, Mineo; Yamanaka, Tatsuru; Yotsumoto, Shigeru; Okamoto, Hiroaki; Tsuda, Fumio; Miyakawa, Yuzo; Matsui, Makoto

doi:10.1203/00006450-199101000-00002

Cited by 109 publications

(66 citation statements)

References 14 publications

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“…7 The reduced chronicity rate of our cWHV8pcmP1 inoculum in neonates (Table 7) may reflect the inability of the infecting virus to produce e antigen, 7 which is believed to act as an immunotolerogen in the neonate. 19,20 Thus, analysis of the uncloned WHV8P1 inoculum for precore mutants and coinfection studies using mixed cWHV8P1 and cWHV8pcmP1 could further address these issues.…”

Section: Discussionmentioning

confidence: 99%

“…The e antigen of HBV has been under study for several years for its potential role as an immunotolerogen 19 and also in association with the natural selection and transmission of e-minus mutants of HBV, some of which may exhibit increased pathogenicity in different settings. 20 Although naturally occurring precore stop codon mutations have been identified among mixed field strains of WHV, 21 the patterns of e-antigen/ antibody seroconversion in WHV infection have not been well studied because the relevant assays have not been developed. Nevertheless, model studies using a genetically engineered e-minus mutant of WHV could help to address some of these issues.…”

Section: A Precore Stop Codon Mutation In Whv Is Associated With Amentioning

confidence: 99%

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Effects of age and viral determinants on chronicity as an outcome of experimental woodchuck hepatitis virus infection

et al. 2000

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Acute hepadnavirus infections either resolve or progress to chronicity. Factors that influence chronicity as an outcome of hepatitis B virus (HBV) infection in humans can be studied experimentally in the woodchuck model. Accordingly, several woodchuck hepatitis virus (WHV) inocula were characterized. Representative inocula had high titers of infectious virus (approximately 10 7.7 -10 9.5 woodchuck 50% infectious doses per milliliter [WID 50% /mL] by subcutaneous inoculation), with 1 WID 50% ranging between 21 and 357 physical virion particles. WHV7P1 (standard high dose, 5 ؋ 10 6 WID 50% ) produced a 72% chronicity rate (i.e., percent chronic of total infected) in neonatal woodchucks (1-3 days old). Comparable doses of WHV8P1 resulted in a lower chronicity rate in neonates (34% chronic) indicating that it represented a strain different from WHV7P1. Neonatal woodchucks were more susceptible to chronic infection by high doses of WHV7P1 (range, 65%-75% chronic) compared with 8-week-old weanlings (33% chronic) and adult woodchucks (0% chronic; i.e., all resolved). High doses of cloned wild-type viruses also induced high rates of chronicity in neonates (70%-80% chronic). Chronicity rates in neonates were decreased for low doses of WHV7P1 (500 WID 50% , 9% chronic) and for high doses of a precore WHeAg-minus mutant WHV8 clone (17% chronic). Thus, both age and viral determinants can influence chronicity as an outcome of experimental WHV infection. Standardized inocula will enable the study of mechanisms that initiate and maintain chronic hepadnavirus infection and also provide a means for developing WHV carriers for therapeutic studies. (HEPATOLOGY 2000;31:190-200.)The eastern woodchuck is naturally infected by a virus closely related to hepatitis B virus (HBV). Experimental infection of woodchucks with woodchuck hepatitis virus (WHV) has been of value in modeling virtually all aspects of HBV infection, pathogenesis, and therapy. 1,2 Development of the model has evolved to use woodchucks bred and reared under controlled environmental conditions, virus-and hostspecific assays for viral infection and disease, and standardized WHV inocula. Because titered HBV inocula have proven invaluable for developing the chimpanzee as a predictive model of HBV infection, disease, and vaccine protection, 3 titered WHV inocula were considered essential for further defining host and viral determinants that promote chronicity and disease progression to hepatocellular carcinoma (HCC) in hepadnavirus infection. In this study, we measured the infectivity of several WHV inocula and, using controlled doses of virus, showed that both animal age and viral determinants can affect chronicity as an outcome of WHV infection. These standardized inocula represent a useful resource for developing serum and tissue banks from selflimited and chronic WHV infections for studies of WHV pathogenesis, and for producing chronic carrier woodchucks at predictable frequencies. MATERIALS AND METHODSAnimals. Woodchucks were bred, maintained, and handled under contr...

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Section: Discussionmentioning

confidence: 99%

Section: A Precore Stop Codon Mutation In Whv Is Associated With Amentioning

confidence: 99%

Effects of age and viral determinants on chronicity as an outcome of experimental woodchuck hepatitis virus infection

et al. 2000

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“…52,53 In woodchucks, mothers with occult woodchuck hepatitis virus transmitted virus to their offspring. 54 Vertical transmission of occult HBV from pregnant woman to the fetus has also been described.…”

Section: Occult Hepatitis B Virus Infectionmentioning

confidence: 99%

Chronic Hepatitis B Virus Infection and Pregnancy

Kumar

Singh

Sinha

2012

Journal of Clinical and Experimental Hepatology

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Planning of pregnancy and management of chronic hepatitis B virus during pregnancy includes recognition of maternal virological status, assessment of liver disease severity and minimization of risk for mother to infant transmission of infection. Decisions regarding the use of antivirals during pregnancy need to be individualized. Monitoring for infection and immunization in newborns is also important. For mothers on antiviral therapy, breastfeeding is not recommended. ( J CLIN EXP HEPATOL 2012;2:366-381) A pproximately 400 million people are chronically infected with hepatitis B virus (HBV) worldwide, 1 and almost half have acquired their infections either through mother to infant transmission or in early childhood, especially in countries where HBV has intermediate to high prevalence.2 In Asia, 8%-10% of the population is chronically infected with HBV, and up to 50% of new cases of hepatitis B infection are due to mother to infant transmission.3 In contrast, the majority of new hepatitis B cases in developed countries are the result of horizontal transmission in adulthood. Before the adoption of standard passive-active immunoprophylaxis treatment, approximately 70%-90% of infants born to hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) positive mothers became chronically infected with HBV. 4 The mother to infant transmission rate was reduced to 5%-10% when infants received appropriate postnatal hepatitis B immunoglobulin (HBIg) and a series of HBV vaccines. However, despite passive-active immunoprophylaxis provided to infants, up to 8%-30% of infants born to highly viremic mothers still become infected with HBV (Figures 1-3). This review will address several issues important to chronic hepatitis B virus infection and pregnancy including effect of pregnancy on chronic HBV infection, effect of chronic HBV infection on pregnancy, mother to infant transmission, safety data on HBV antivirals during pregnancy, management of chronic HBV infection in women who desire pregnancy or become pregnant while taking antivirals. PREVALENCE OF CHRONIC HEPATITIS B VIRUS INFECTION AMONG PREGNANT WOMEN IN INDIAThe prevalence of chronic HBV infection varies widely, with rates ranging from 0.1% to 20% in different parts of the world.2 "High" prevalence (HBsAg positivity rates > 8%) regions include the Asia (except Japan), parts of the Middle East, sub-Saharan Africa, and the Amazon basin. "Intermediate" (2%-7% HBsAg positive) prevalence regions include, the Indian subcontinent, parts of central Asia and the Middle East, Eastern and Southern Europe, as well as parts of South America. "Low" prevalence (<2% HBsAg positive) regions include the United States, Northern Europe, Australia, Japan and the southern part of South America. Overall, 45% of the world population lives in "high" prevalence regions.The HBsAg positivity rate of Hepatitis B in India is different in the different regions of the country. The overall chronic HBsAg positivity rate is often quoted as being 4.7%.5 In India, the prevalence rate of HBsAg...

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“…4 Perinatal transmission of HBV by eantigen positive mothers correlates with a high incidence of chronicity in the offspring. 5,6 Furthermore, in adults with chronic HBV infection, e-antigen positivity has been linked to the elimination of e-antigen and core-antigen specific T-cells thus favoring viral persistence. 7 While the role of e-antigen in regulating the immune system is only partially understood, 8,9 its high evolutionary conservation in the Hepadnaviridae suggests the importance of its function.…”

Section: Introductionmentioning

confidence: 99%

Assessment of differences in the conformational flexibility of hepatitis B virus core‐antigen and e‐antigen by hydrogen deuterium exchange‐mass spectrometry

et al. 2014

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Hepatitis B virus core-antigen (capsid protein) and e-antigen (an immune regulator) have almost complete sequence identity, yet the dimeric proteins (termed Cp149 d and Cp(210)149 d , respectively) adopt quite distinct quaternary structures. Here we use hydrogen deuterium exchange-mass spectrometry (HDX-MS) to study their structural properties. We detect many regions that differ substantially in their HDX dynamics. Significantly, whilst all regions in Cp(210)149 d exchange by EX2-type kinetics, a number of regions in Cp149 d were shown to exhibit a mixture of EX2-and EX1-type kinetics, hinting at conformational heterogeneity in these regions.Comparison of the HDX of the free Cp149 d with that in assembled capsids (Cp149 c ) indicated increased resistance to exchange at the C-terminus where the inter-dimer contacts occur. Furthermore, evidence of mixed exchange kinetics were not observed in Cp149 c , implying a reduction in flexibility upon capsid formation. Cp(210)149 d undergoes a drastic structural change when the intermolecular disulphide bridge is reduced, adopting a Cp149 d -like structure, as evidenced by the detected HDX dynamics being more consistent with Cp149 d in many, albeit not all, regions. These results demonstrate the highly dynamic nature of these similar proteins. To probe the effect of these structural differences on the resulting antigenicity, we investigated binding of the antibody fragment (Fab E1) that is known to bind a conformational epitope on the four-helix bundle. Whilst Fab E1 binds to Cp149 c and Cp149 d , it does not bind non-reduced and reduced Cp (210)149 Published by Wiley-Blackwell. V C 2014 The Protein Society despite unhindered access to the epitope. These results imply a remarkable sensitivity of this epitope to its structural context.

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Hepatitis B Virus Mutants with Precore-Region Defects in Two Babies with Fulminant Hepatitis and Their Mothers Positive for Antibody to Hepatitis B e Antigen

Cited by 109 publications

References 14 publications

Effects of age and viral determinants on chronicity as an outcome of experimental woodchuck hepatitis virus infection

Effects of age and viral determinants on chronicity as an outcome of experimental woodchuck hepatitis virus infection

Chronic Hepatitis B Virus Infection and Pregnancy

Assessment of differences in the conformational flexibility of hepatitis B virus core‐antigen and e‐antigen by hydrogen deuterium exchange‐mass spectrometry

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