Archives of virology. Supplementum (Arch Virol Suppl)

Publications in this journal

• Article: Immune evasion mechanisms of varicella-zoster virus.

  A Abendroth, A Arvin
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  ABSTRACT: Varicella-zoster virus can to modulate the expression of class I and class II major histocompatibility (MHC) molecules. MHC class I expression is downregulated in VZV-infected T cells as well as in fibroblasts. VZV-infected cells do not respond to exposure to interferon-gamma (IFN-gamma) by upregulation of MHC class II expression. However, MHC class II expression is induced when cells are treated with IFN-gamma before VZV infection. These effects on MHC class I and class II expression can be expected to interfere transiently with adaptive immune responses of the host, mediated by CD4 and CD8 T cells, ensuring that the virus has sufficient opportunity for transmission to susceptible contracts.
  Archives of virology. Supplementum 02/2001;
• Article: The current status of live attenuated varicella vaccine.

  A A Gershon
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  ABSTRACT: This manuscript reviews the means by which live attenuated varicella vaccine offers protection against varicella and zoster. It is accepted that although varicella is usually a mild illness, complications leading to morbidity and mortality are significant and the disease is worth preventing. The vaccine offers close to 100% protection from severe chickenpox and 90% protection from illness. Waning of immunity after vaccination, particularly in children, has not been a significant problem. Ways in which vaccination may decrease the incidence and severity of zoster include the following. Vaccine virus may be less likely to establish latency and to be able to reactivate than wild type virus. In addition, by selective immunization of certain hosts such as HIV-infected children whose, immune systems are still relatively intact and individuals with latency due to wild type virus to boost the cell-mediated immune response to the virus, zoster may be decreased. Varicella vaccine is predicted to have a major impact on the epidemiology of varicella and zoster in countries with high vaccine uptake.
  Archives of virology. Supplementum 02/2001;
• Article: Use of varicella vaccines to prevent herpes zoster in older individuals.

  M J Levin
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  ABSTRACT: It is likely that the frequency and severity of herpes zoster in older people is the result of an age-related decline in varicella-zoster virus-specific T-cell mediated immunity. Numerous trials of vaccines to boost these responses have demonstrated their safety and immunogenicity. Both live attenuated and inactivated vaccines have been studied. Persistence of booster responses is dose-related, and the half-life of some boosted measures of T-cell mediated immunity exceeds 5 years. Although these trials have been hampered by uncertainty about the critical immune responses to evaluate, the stage is set for a double-blind, placebo-controlled trial of sufficient size to determine efficacy. Such a trial is now underway.
  Archives of virology. Supplementum 02/2001;
• Article: Varicella-zoster virus with a lost gE epitope: evidence for immunological pressure by the human antibody response.

  J A Padilla, C Grose
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  ABSTRACT: The varicella-zoster virus (VZV) genome contains about 70 open reading frames (ORF). ORF 68 codes for glycoprotein gE, formerly called gpl, which is the predominant VZV glycoprotein; gE is a typical type 1 transmembrane protein with 623 amino acids. Recently, a variant virus was discovered which has a mutation in gE codon 150; this mutation converts an aspartic acid into an asparagine residue.
  Archives of virology. Supplementum 02/2001;
• Article: Varicella-zoster virus immunity and prevention: a conference perspective.

  S E Straus
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  ABSTRACT: This report offers a concise overview of the VZV Conference, highlighting recent developments in the field and speculating on areas of greatest opportunity and need for future work. The goal of eradicating VZV disease will be facilitated by a multifaceted research agenda directed at a fuller comprehension of how the virus replicates, spreads and persists, and how it eludes host immune responses.
  Archives of virology. Supplementum 02/2001;
• Article: Mutagenesis of the varicella-zoster virus genome: lessons learned.

  J I Cohen
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  ABSTRACT: The varicella-zoster virus (VZV) genome encodes at least 70 genes. We have developed a cosmid based system to inactivate individual viral genes or to insert foreign genes into the genome. We have shown that many VZV genes are not required for replication of the virus in cell culture. Several of these genes, including VZV ORF61, ORF47, and ORF10, have unexpected phenotypes in cell culture and differ from their homologs in the better studied herpes simplex virus (HSV). We have also used the Oka strain of VZV as a live virus vaccine vector. Guinea pigs vaccinated with recombinant VZV expressing HSV-2 glycoprotein D and challenged with HSV-2 have reduced severity of primary genital herpes and reduced mortality compared to animals receiving parental VZV. Recently we have inserted the human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) glycoprotein 160 genes into the Oka strain of VZV and have shown that these proteins are expressed in recombinant virus-infected cells. Thus, directed mutagenesis of the VZV genome is providing new insights into viral pathogenesis and may provide new candidate vaccines.
  Archives of virology. Supplementum 02/2001;
• Article: Vaccination against cytomegalovirus.

  S A Plotkin
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  ABSTRACT: Like varicella zoster virus (VZV), human cytomegalovirus (HCMV) causes disease after both primary and recurrent infections. The former is more serious, particularly in pregnant women, who may transmit the virus to their offspring, with a high risk of mental retardation and deafness. Various experimental vaccines are in development, ranging from live, attenuated HCMV, subunit envelope glycoprotein, poxvirus vectors with CMV genes inserted, and plasmid DANN.
  Archives of virology. Supplementum 02/2001;
• Article: Comparison of DNA sequence and transactivation activity of open reading frame 62 of Oka varicella vaccine and its parental viruses.

  Y Gomi, T Imagawa, M Takahashi, K Yamanishi
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  ABSTRACT: When nucleotide sequences of Oka vaccine and its parental viruses of varicella-zoster virus (VZV) were compared in 5 open reading frames (ORFs) including glycoprotein C (gC) and 4 immediate-early genes, mutations were detected only in gene 62 which is one of the immediate-early genes. Compared with its parental virus, the vaccine virus contained 15 nucleotide substitutions. With the differentiation method using the simplified restriction-enzyme fragment length polymorphism analysis by Nae I and Bss HII, which was established based on the sequence analysis data in this study, the Oka vaccine virus could be distinguished from its parental virus. Studies of the regulatory activities of the ORF62 gene product (IE62) in a transient assay indicate the IE62 of the parental virus had a stronger transactivational activity than that of the vaccine virus against immediate-early, early and late gene promoters. These data suggest that gene 62 might have an important role for attenuation of VZV. This is the first report in which many substitutions of nucleotides in gene 62 of Oka vaccine virus was found, compared with that of Oka parental virus.
  Archives of virology. Supplementum 02/2001;
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  Article: The role of varicella zoster virus immediate-early proteins in latency and their potential use as components of vaccines.

  C Sadzot-Delvaux, B Rentier
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  ABSTRACT: Varicella zoster virus immediate-early (IE) proteins are intracellular regulators of viral gene expression. Some of them (IE62 and IE63) are found in large amounts in infected cells but are also components of the virion tegument. Several IE and early genes are transcribed during latency, while late genes are not. Recently, we demonstrated the presence of protein IE 63 in dorsal root ganglia of persistently infected rats as well as in normal human ganglia; other IE proteins have been found since in human ganglia. Cell-mediated immunity (CMI) to IE 62 has been evidenced. We found both humoral immunity and CMI to IE 63 in immune adults. In elderly zoster-free individuals, CMI to IE 63 remained high. The differences in the CMI to IE 63 among young adults, elderly people and immunocompromized patients have to be analyzed according to their status relative to zoster, to determine whether the decrease in CMI, particularly to IE proteins, could be responsible for viral reactivation and for the onset of shingles. Hopefully, the waning of the CMI to VZV IE 63 and perhaps to other IE proteins could become a predictive marker for herpes zoster and reimmunization, not only with the vaccine strain, but also with purified IE proteins could help prevent zoster at old age.
  Archives of virology. Supplementum 02/2001;
• Article: Biologic and geographic differences between vaccine and clinical varicella-zoster virus isolates.

  P S Larussa, A A Gershon
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  ABSTRACT: Vaccine and wild-type strains of varicella-zoster virus differ both in their biologic characteristics and in the clinical manifestations of infection caused by each strain. The biologic differences described for the vaccine strain (temperature sensitivity and host cell preference) probably reflect the methods used to adapt the wild-type strain to the in vitro growth conditions imposed during the attenuation process in cell culture. In addition, restriction fragment polymorphisms have been described that reflect geographic strain variations between the parental virus used to develop the vaccine strain and other wild-type strains. These polymorphisms have been exploited as tools for the identification and differentiation of vaccine and wild-type strains in clinical studies. Infection with the wild-type strain results in the typical extensive rash of varicella, frequent transmission to other susceptible contacts, establishment of latency, and in some individuals, reactivation with the clinical picture of zoster. Infection with the vaccine strain results in the development of a protective immune response, minimal rash in a minority of individuals, rare transmission to other susceptible contacts, and a greatly reduced risk of zoster.
  Archives of virology. Supplementum 02/2001;
• Article: Cis and trans elements regulating expression of the varicella zoster virus gI gene.

  H He, D Boucaud, J Hay, W T Ruyechan
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  ABSTRACT: We have identified cis- and trans-acting elements involved in the VZV IE62 protein-activated expression of the varicella zoster virus (VZV) gene which encodes the viral gI glycoprotein. The cis-acting elements include a non-canonical TATA box and a novel 19 base pair sequence located just upstream of the TATA element designated the "activating upstream sequence" or AUS. The AUS is a movable element and its presence results in IE62 activation of a chimeric promoter consisting of the VZV gC TATA box and the gI AUS. We have also determined that the VZV ORF 29 protein modulates the regulatory activity of the IE62 protein at the gI promoter. In combination with the IE62 transactivator, it yields a 10 to 15-fold increase in expression over the levels seen with the IE62 protein alone in T lymphocytes. The upmodulatory activity requires the presence of a 40 base pair sequence, designated the 29RE, which maps between positions -220 and -180 in the gI promoter. In this paper we review these and earlier findings from our laboratories concerning the regulation of the gI promoter.
  Archives of virology. Supplementum 02/2001;
• Article: Evidence for frequent reactivation of the Oka varicella vaccine strain in healthy vaccinees.

  P R Krause
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  ABSTRACT: Serum antibody levels and infection rates were followed for 4 years in 4,631 children immunized with the recently licensed Oka strain varicella vaccine. Anti-VZV titers declined over time in high-responder subjects, but rose in vaccinees with low titers. Among subjects with low anti-VZV titers, the frequency of clinical sequelae and immunological boosting significantly exceeded the 13%/yr rate of exposure to wild type varicella. These findings indicate that the Oka strain of VZV persisted in vivo, and reactivated as serum antibody titers declined after vaccination. This mechanism may improve vaccine-associated long-term immunity.
  Archives of virology. Supplementum 02/2001;
• Article: In vitro measurement of human T cell responses to varicella zoster virus antigen.

  A R Hayward
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  ABSTRACT: Means to quantitate cell-mediated immunity are increasingly in demand as modifications to existing vaccines and new vaccines are tested. For immunity to varicella zoster virus, there is over a decade of experience with estimates of responder cell frequency obtained by diluting the number of lymphocytes in antigen-stimulated cultures. This method shows substantial variations between subjects, so populations of 12 or more subjects per group are needed to make comparisons possible. Cytokine-based methods for T lymphocyte responses may prove more sensitive, as may direct antigen-binding methods using tetramers of peptide and histocompatibility antigens--but experience with both is very limited.
  Archives of virology. Supplementum 02/2001;
• Article: Pathway of viral spread in herpes zoster: detection of the protein encoded by open reading frame 63 of varicella-zoster virus in biopsy specimens.

  T Iwasaki, R Muraki, T Kasahara, Y Sato, T Sata, T Kurata
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  ABSTRACT: Reactivation of varicella-zoster virus (VZV) in the dorsal root or trigeminal ganglia causes herpes zoster. The pathway of viral spread from the ganglia to the skin and also within the skin is not yet completely understood. Histological studies have revealed that each skin lesion in herpes zoster progresses sequentially through the stages of erythema, vesicles, pustules and finally ulceration. An immunohistochemical study of the early skin lesions of herpes zoster demonstrated a high incidence of hair follicle involvement and the main localization of the virus at the isthmus. This evidence suggests that VZV initially spreads from the ganglia through myelinated nerves, which predominantly end around the isthmus of hair follicles. To further investigate the viral spread within the skin, we analyzed the sequential appearance of the immediate early proteins encoded by ORF 63 of VZV (IE63), using an anti-IE63 antibody raised by immunization of rabbits with a recombinant protein. This antibody could detect IE63 in a western blot analysis of infected cells and also in immunohistochemical analysis of the skin lesions of herpes zoster. IE63 initially appeared in the nuclei of the follicular epithelial cells and basal or parabasal epidermal cells. Later, the nuclei and cytoplasm of cells in the epidermis and hair follicles became positive. IE63 remained in the virus-infected cells even during their degeneration. When we examined the hair follicles in the early erythematous lesions, cells positive for IE63 were predominantly distributed around the isthmus. In addition, some lymphocytes around the blood vessels were also positive for IE63, but these cells were seldom positive for the structural antigen. Thus, these observations suggest that VZV arriving through myelinated nerves infects not only permissive cells, but also non-permissive cells in the involved skin of herpes zoster.
  Archives of virology. Supplementum 02/2001;
• Article: Immunization of the elderly to boost immunity against varicella-zoster virus (VZV) as assessed by VZV skin test reaction.

  M Takahashi, H Kamiya, Y Asano, K Shiraki, K Baba, T Otsuka, T Hirota, K Yamanishi
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  ABSTRACT: The utility of the VZV skin test in detecting individual susceptibility to varicella and zoster was determined. Its specificity particularly with regard to herpes simplex was also established. The VZV skin test was negative or weakly positive during the early stage of herpes zoster, and strongly positive during recovery from that disease. A small-scale clinical trial to immunize elderly individuals has been performed for the purpose of preventing herpes zoster, and, perhaps, severe post-herpetic neuralgia as well. Sixty individuals > or = 50 years old were screened for VZV antibodies by IAHA test and were given a VZV skin test for cell-mediated immunity. All were seropositive, but eight were skin-test negative. Thirty-seven individuals including the eight with negative skin tests were immunized with one dose of varicella vaccine (3.0 x 10(4) PFU/dose). After 5-7 weeks, the skin test reaction showed increased positivity, with a change in score from (-) to (+, ++) in 7/8 subjects, from (+) to (++, +++) in 3/5 subjects, and from (++) to (+++) in 6/10 subjects. Enhancement of the VZV antibody titer (defined as twofold or greater) was observed in all 15 vaccine recipients with a prevaccination titer of < or = 1:16, and in 19 of 24 subjects with a prevaccination titer of > or = 1:32. These results indicate that giving live varicella vaccine with a high viral titer can induce a good boost immunity particularly cell-mediated immunity to VZV in the elderly.
  Archives of virology. Supplementum 01/2001;
• Article: Analyzing the influence of PrP primary structure on prion pathogenesis in transgenic mice.

  S Campbell, U Dennehy, G Telling
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  ABSTRACT: Expression of prion protein (PrP) genes in transgenic (Tg) mice has been an extremely effective means of studying human and animal prion diseases. Indeed, much of what we currently understand about the molecular basis of prion pathogenesis derives from such studies. Despite these advances, the emergence of a new variant of Creutzfeldt-Jakob disease (vCJD), apparently the human manifestation of bovine spongiform encephalopathy (BSE), demonstrates that our understanding of the factors controlling prion transmission is far from complete. We review studies in Tg mice that have addressed issues of prion strains and species barriers and have provided insights into mechanisms of prion propagation. The goal of future investigation will be to determine the interplay between PrP primary structure and conformation in determining prion transmission barriers and we discuss some ongoing transgenic studies designed to address these issues.
  Archives of virology. Supplementum 02/2000;
• Article: PrP(Sc) typing by N-terminal sequencing and mass spectrometry.

  S G Chen, W Zou, P Parchi, P Gambetti
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  ABSTRACT: The heterogeneity of the clinicopathological phenotype in human prion diseases is associated with the presence of the different forms of the abnormal prion protein, PrP(Sc). We have previously shown that PrP(Sc) in FFI and a subtype of familial CJD linked to the D178N mutation can be distinguished by their difference in gel mobility following proteinase K (PK) treatment. To further characterize the structural difference of PrP(Sc) in familial prion diseases, N-terminal sequencing and mass spectrometry were used to identify the protease cleavage sites in PrP(Sc) extracted from affected brains. We found that the main PK cleavage sites of PrP(Sc) are located at residue 97 in FFI, and residue 82 in both CJD178 and a GSS subtype linked to the P102L mutation. The differential accessibility to protease in the native PrP(Sc) suggests that PrP(Sc) exist as distinct conformers in different disease states.
  Archives of virology. Supplementum 02/2000;
• Article: Quantitative traits of prion strains are enciphered in the conformation of the prion protein.

  J Safar, F E Cohen, S B Prusiner
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  ABSTRACT: Variations in prions, which cause different disease phenotypes, are often referred to as strains. Strains replicate with a high degree of fidelity, which demands a mechanism that can account for this phenomenon. Prion strains differ by qualitative characteristics such as clinical symptoms, brain pathology, topology of accumulated PrP(Sc), and Western blot patterns of glycosylated or deglycosylated PrP(Sc). Since none of these qualitative features can directly explain quantitative strain traits such as incubation time or dose response, we analyzed conformational parameters of PrP(Sc) and the rate of accumulation in different prion strains. Using the conformation-dependent immunoassay (CDI), we were able to discriminate among PrP(Sc) molecules from eight different prion strains propagated in Syrian hamsters. CDI quantifies PrP isoforms by simultaneously following antibody binding to both the denatured and native forms of a protein. In a plot of the ratio of antibody binding to denatured/native PrP graphed as a function of the concentration of PrP(Sc), each strain occupied a unique position, indicating that each strain accumulated different concentrations of particular PrP(Sc) conformers. This conclusion was supported by a unique pattern of equilibrium unfolding of PrP(Sc) found within each strain. By comparing the PrP(Sc) levels before and after limited proteinase K digestion, we found that each strain produces a substantial fraction of protease-sensitive PrP(Sc). We asked whether this fraction of PrP(Sc) might reflect those PrP(Sc) molecules that are most readily cleared by cellular proteases. When the protease-sensitive PrP(Sc) fraction was plotted as a function of the incubation time, a linear relationship was found with an excellent correlation coefficient (r = 0.94). Combined with the data on time courses of prion infection in Tg(MHu2M) and Tg(SHaPrP) mice, the results argue that different incubation times of various prion strains may arise predominantly from distinct rates of PrP(Sc) clearance rather than from different rates of PrP(Sc) formation.
  Archives of virology. Supplementum 02/2000;
• Article: Pathogenesis of natural scrapie in sheep.

  L J van Keulen, B E Schreuder, M E Vromans, J P Langeveld, M A Smits
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  ABSTRACT: Although scrapie has been known for a long time as a natural disease of sheep and goats, the pathogenesis in its natural host still remains unclear. To study the pathogenesis of natural scrapie, we used immunohistochemistry to monitor the deposition of PrP(Sc) in various tissues, collected during a natural scrapie infection from sheep with the PrP(VRQ)/PrP(VRQ) genotype which were purposely bred for their short incubation period for natural scrapie. PrP(Sc) was present in the lymphoid tissues of all animals from the age of 5 months onwards. At this age, PrP(Sc) was detected in the neural tissues only in the enteric nervous system (ENS) at the level of the duodenum and ileum. At the age of 10 months, PrP(Sc) was not only found in the ENS but also in the ganglion mesentericum cranialis/coeliacum, the dorsal motor nucleus of the vagus, and the intermediolateral column of the thoracic segments T8-T10. PrP(Sc) was detected for the first time in the nucleus tractus solitarius and ganglion nodosus at 17 months of age and in the ganglion trigeminale and several spinal ganglia at 21 months of age. Since the scrapie agent consists largely, if not entirely of PrP(Sc), these results indicate that the ENS acts as a portal of entry to the neural tissues for the scrapie agent followed by centripetal and retrograde spread through sympathetic and parasympathetic efferent fibers of the autonomic nervous system to the spinal cord and medulla oblongata respectively. PrP(Sc) accumulation in sensory ganglia occurs after infection of the CNS and is therefore probably due to centrifugal and anterograde spread of the scrapie agent from the CNS through afferent nerve fibers.
  Archives of virology. Supplementum 02/2000;