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Biomedical subjects

Anne A Gershon

Publications and source records attributed to Anne A Gershon.

At least 19 recordsLinked to original sources
PubMed2007

Recommendations for the management of herpes zoster.

The objective of this article is to provide evidence-based recommendations for the management of patients with herpes zoster (HZ) that take into account clinical efficacy, adverse effects, impact on quality of life, and costs of treatment. Systematic literature reviews, published randomized clinical trials, existing guidelines, and the authors' clinical and research experience relevant to the management of patients with HZ were reviewed at a consensus meeting. The results of controlled trials and the clinical experience of the authors support the use of acyclovir, brivudin (where available), famciclovir, and valacyclovir as first-line antiviral therapy for the treatment of patients with HZ. Specific recommendations for the use of these medications are provided. In addition, suggestions are made for treatments that, when used in combination with antiviral therapy, may further reduce pain and other complications of HZ.

2-Aminopurine↗
PubMed2006

Natural selection for rash-forming genotypes of the varicella-zoster vaccine virus detected within immunized human hosts.

The Oka vaccine strain is a live attenuated virus that is routinely administered to children in the United States and Europe to prevent chickenpox. It is effective and safe but occasionally produces a rash. The vaccine virus has accumulated mutations during its attenuation, but the rashes are not explained by their reversion, unlike complications reported for other viral vaccines. Indeed, most of the novel mutations distinguishing the Oka vaccine from the more virulent parental virus have not actually become fixed. Because the parental alleles are still present, the vaccine is polymorphic at >30 loci and therefore contains a mixture of related viruses. The inoculation of >40 million patients has consequently created a highly replicated evolutionary experiment that we have used to assess the competitive ability of these different viral genotypes in a human host. Using virus recovered from rash vesicles, we show that two vaccine mutations, causing amino acid substitutions in the major transactivating protein IE62, are outcompeted by the ancestral alleles. Standard interpretations of varicella disease severity concentrate on the undeniably important effects of host genotype and immune status, yet our results allow us to demonstrate that the viral genotype is associated with virulence and to identify the key sites. We propose that these loci have pleiotropic effects on the immunogenic properties of the virus, rash formation, and its epidemiological spread, which mould the evolution of its virulence. These findings are of practical importance for reducing the incidence of vaccine-associated rash and promoting public acceptance of the vaccine.

Chickenpox Vaccine↗
PubMed2006

Administration of live varicella vaccine to HIV-infected children with current or past significant depression of CD4(+) T cells.

BACKGROUND: Varicella can be a severe illness in human immunodeficiency virus (HIV)-infected children. The licensed, live attenuated varicella vaccine is safe and immunogenic in HIV-infected children with minimal symptoms and good preservation of CD4(+) T cells (Centers for Disease Control and Prevention immunologic category 1). METHODS: To study the safety and immunogenicity of this vaccine in varicella-zoster virus (VZV)-naive, HIV-infected children with moderate symptoms and/or more pronounced past or current decreases in CD4(+) T cell counts, such children (age, 1-8 years) received 2 doses of vaccine 3 months apart. The children were observed in a structured fashion for adverse events. Blood was tested for VZV antibody and VZV-specific cell-mediated immunity (CMI) at baseline, 8 weeks after each dose, and annually for 3 years. Subjects who had no evidence of immunity 1 year after vaccination received a third dose and were retested. RESULTS: The vaccine was well tolerated; there were no vaccine-related, serious adverse events. Regardless of immunologic category, at least 79% of HIV-infected vaccine recipients developed VZV-specific antibody and/or CMI 2 months after 2 doses of vaccine, and 83% were responders 1 year after vaccination. CONCLUSIONS: HIV-infected children with a CD4(+) T cell percentage of > or =15% and a CD4(+) T cell count of > or =200 cells/ microL are likely to benefit from receiving varicella vaccine.

Anti-HIV Agents↗
PubMed2006

Vaccine Oka varicella-zoster virus genotypes are monomorphic in single vesicles and polymorphic in respiratory tract secretions.

We previously found that, after immunization with vaccine Oka varicella-zoster virus, virus obtained from a single vesicle were monomorphic, and virus obtained from different individuals were heterogeneous. Here we show that virus obtained from the lungs of a patient were a mixture of vaccine Oka variants. We hypothesize that complications after immunization are unlikely to be caused by expansion of a single, biologically more virulent clone of virus that either pre-exists in the vaccine or develops after random mutation of different clones. We hypothesize that some clones are more trophic than others for skin.

Chickenpox↗
PubMed2006

The cellular localization pattern of Varicella-Zoster virus ORF29p is influenced by proteasome-mediated degradation.

Varicella-zoster virus (VZV) open reading frame 29 (ORF29) encodes a single-stranded DNA binding protein. During lytic infection, ORF29p is localized primarily to infected-cell nuclei, whereas during latency it appears in the cytoplasm of infected neurons. Following reactivation, ORF29p accumulates in the nucleus. In this report, we analyze the cellular localization patterns of ORF29p during VZV infection and during autonomous expression. Our results demonstrate that ORF29p is excluded from the nucleus in a cell-type-specific manner and that its cellular localization pattern may be altered by subsequent expression of VZV ORF61p or herpes simplex virus type 1 ICP0. In these cases, ORF61p and ICP0 induce nuclear accumulation of ORF29p in cell lines where it normally remains cytoplasmic. One cellular system utilized by ICP0 to influence protein abundance is the proteasome degradation pathway. Inhibition of the 26S proteasome, but not heat shock treatment, resulted in accumulation of ORF29p in the nucleus, similar to the effect of ICP0 expression. Immunofluorescence microscopy and pulse-chase experiments reveal that stabilization of ORF29p correlates with its nuclear accumulation and is dependent on a functional nuclear localization signal. ORF29p nuclear translocation in cultured enteric neurons and cells derived from an astrocytoma is reversible, as the protein's distribution and stability revert to the previous states when the proteasomal activity is restored. Thus, stabilization of ORF29p leads to its nuclear accumulation. Although proteasome inhibition induces ORF29p nuclear accumulation, this is not sufficient to reactivate latent VZV or target the immediate-early protein ORF62p to the nucleus in cultured guinea pig enteric neurons.

Amino Acid Sequence↗
PubMed2005

An evaluation of single nucleotide polymorphisms used to differentiate vaccine and wild type strains of varicella-zoster virus.

Rashes following immunization with the vaccine strain (vOka) of varicella-zoster virus (VZV) may occur in up to 5% of children and 10% of adults. In 40% of cases, the causative virus is the vaccine strain and in 60% wild type virus is found. Several reports have identified three restriction site polymorphisms in ORF 62 and the loss of one in ORF 6, which differentiate vOka from wild type VZV, including the parental wild type strain from which vOka, is derived. Using polymerase chain reaction (PCR), restriction enzyme analysis, and sequencing, we analyzed the presence of these markers in the GlaxoSmithKline (GSK, UK) and Merck vaccine preparations as well as in 15 vaccine virus rashes and 15 wild type UK viruses. Our data suggest that a Sma1 positive and an Nae1 positive site in ORF 62 are present in the GSK and Merck vaccine preparations and all vaccine virus rashes. By contrast, a BssHII positive vaccine virus restriction site in ORF 62 and an Alu1 negative site in ORF 6 were mixed in the GSK and Merck vaccines and absent in some of the vaccine rashes. The BssHII site was also present in the European wild type C viruses in UK. The data suggest that unlike the Biken vaccine preparation, the Merck and GSK vaccine preparations are polymorphic for the BssHII and Alu1 restriction sites. These sites are also present variably in the vaccine viruses causing rashes following vaccination, and are therefore unreliable markers for differentiating vOka and wild type VZV strains.

Chickenpox↗
PubMed2005

The impact of varicella vaccination in the United States.

The addition of varicella vaccine to the universal childhood immunization schedule in the United States in 1995 can be seen as a bold step. Shown to be safe and efficacious against varicella in extensive prelicensure studies, it is nonetheless the first vaccine against a herpesvirus and, furthermore, it is a live, attenuated vaccine. Both wild-type and vaccine strain varicella zoster virus (VZV) are noteworthy for their ability to establish latent infection within the host, with the subsequent possibility of reactivation. Therefore, at the population level, a successful vaccination program could result in the eventual displacement of wild-type VZV by the attenuated vaccine virus. The immediate objective of universal vaccination, however, was to reduce the significant morbidity and mortality associated with primary VZV infection. Data now accumulating suggest that the varicella vaccine as used in the United States has so far been highly effective. The challenge for the future is to predict how the resulting substantial reduction in circulation of VZV will affect immunity among both vaccinees and the unvaccinated. Vaccination strategies likely will need to be adjusted as the epidemiology of VZV in the United States continues to evolve.

Adult↗
PubMed2005

Preventing varicella-zoster disease.

Varicella-zoster virus (VZV), the cause of chickenpox and shingles, is a pathogen in retreat following the introduction of mass vaccination in the United States in 1995. The live attenuated Oka vaccine, which is safe and immunogenic, gives good protection against both varicella and zoster in the short to medium term. It has undoubtedly been highly effective to date in reducing all forms of varicella, especially severe disease. However, the huge pool of latent wild-type virus in the population represents a continuing threat. Both the biology and the epidemiology of VZV disease suggest that new vaccination strategies will be required over time.

Adolescent↗
PubMed2004

Mannose 6-phosphate receptor dependence of varicella zoster virus infection in vitro and in the epidermis during varicella and zoster.

Varicella zoster virus (VZV) is a highly infectious human pathogen; nevertheless, infectious virions are not released in vitro where infection is cell associated. Four VZV envelope glycoproteins contain mannose 6-phosphate (Man 6-P), and Man 6-P blocks infection of cells by cell-free VZV. Expression of antisense cDNA or siRNA-like transcripts were used to generate five stable human cell lines deficient in cation-independent mannose 6-phosphate receptors (MPRci). All 5 MPRci-deficient lines resisted infection by cell-free, but not cell-associated, VZV, secreted lysosomal enzymes, and released infectious virions when infected by cell-associated VZV. Intracellular MPRci thus appear to divert newly enveloped VZV to late endosomes, and plasmalemmal MPRci are necessary for entry by cell-free VZV. Biopsies from VZV-infected human skin supported the idea that because MPRci expression is naturally lost in maturing superficial epidermal cells, these cells do not divert VZV to endosomes and constitutively secrete infectious VZV.

Cell Line, Tumor↗
PubMed2004

Rashes occurring after immunization with a mixture of viruses in the Oka vaccine are derived from single clones of virus.

Vaccination against chickenpox causes a varicella-like rash in up to 5% of healthy children and 50% of children with leukemia. The vaccine may establish latency and reactivate to cause herpes zoster, albeit more rarely than wild-type virus. All vaccine preparations are composed of a mixture of varicella-zoster virus strains that show genotypic variation at several loci. We have shown, by DNA sequencing of 40 polymorphic loci, that viruses sampled from vesicles in varicella-like and herpes zoster rashes are single clones. This finding suggests that, between the time of inoculation of the vaccine and development of rash, selection of single strains occurs. The results have general implications for the pathogenesis of varicella-zoster virus.

Adolescent↗
PubMed2004

Effectiveness over time of varicella vaccine.

CONTEXT: Reports of outbreaks of varicella in highly immunized groups have increased concern about the effectiveness of varicella vaccine. OBJECTIVE: To assess whether the effectiveness of varicella vaccine is affected either by time since vaccination or by age at the time of vaccination. DESIGN: Case-control study conducted from March 1997 through June 2003. SETTING: Twenty different group practices in southern Connecticut. PARTICIPANTS: Case subjects, identified by active surveillance of all practices, consisted of 339 eligible children 13 months or older who were clinically diagnosed as having chickenpox and who also had a polymerase chain reaction (PCR) test result that was positive for varicella-zoster virus DNA. For each case subject, 2 controls were selected, matched by both age and pediatric practice. MAIN OUTCOME MEASURES: The effectiveness of the vaccine, especially the effects of time since vaccination and age at the time of vaccination, adjusted for possible confounders. RESULTS: Although the adjusted overall effectiveness of the vaccine was 87% (95% confidence interval, 81%-91%; P<.001), there was a substantial difference in the vaccine's effectiveness in the first year after vaccination (97%) and in years 2 to 8 after vaccination (84%, P =.003). The vaccine's effectiveness in year 1 was substantially lower if the vaccine was administered at younger than 15 months (73%) than if it was administered at 15 months or older (99%, P =.01), although the difference in effectiveness overall for children immunized at younger than 15 months was not statistically significantly different than for those immunized at 15 months or older (81% vs 88%, P =.17). Most cases of chickenpox in vaccinees were mild. CONCLUSIONS: Although varicella vaccine is effective, its effectiveness decreases significantly after 1 year, although most cases of breakthrough disease are mild. If administered at younger than 15 months, the vaccine's effectiveness was lower in the first year after vaccination, but the difference in effectiveness was not statistically significant for subsequent years.

Adolescent↗
PubMed2004

Consensus: varicella vaccination of healthy children--a challenge for Europe.

The seriousness of varicella-zoster virus (VZV) infection as a public health issue is becoming clearer as country-specific epidemiologic and pharmacoeconomic data become available. In Germany, for example, studies have shown that >5.5% of immunologically healthy individuals develop varicella-related complications such as bacterial superinfections, acute neurologic disorders, pneumonia, bronchitis and otitis media; whereas in Italy, 3.5 to 5% of childhood cases of varicella cause complications such as upper respiratory tract and cutaneous infections. Varicella vaccines are now available. These live attenuated Oka strain vaccines have been shown in extensive studies to be highly immunogenic and well-tolerated in immunocompetent and immunocompromised children, with seroconversion rates ranging from 94 to 100% and 53 to 100%, respectively. These vaccines are also highly effective against clinical disease. These considerations led to a reevaluation of varicella vaccination policies. A routine varicella vaccination program targeting healthy children has already been implemented in the US, and data produced are encouraging and valuable. Similar strategies have not yet been adopted across Europe. The European Working Group on Varicella (EuroVar) was formed in 1998 to address the issues surrounding varicella epidemiology in Europe. After a series of meetings, the EuroVar members prepared a consensus statement recommending routine varicella vaccination for all healthy children between 12 and 18 months and to all susceptible children before their 13th birthday, in addition to catch-up vaccination in older children and adults who have no reliable history of varicella and who are at high risk of transmission and exposure. However, such a policy is recommended only if a very high coverage rate can be achieved. This could be reached with a measles-mumps-rubella-varicella combined vaccine.

Adolescent↗
PubMed2003

Latent and lytic infection of isolated guinea pig enteric ganglia by varicella zoster virus.

Varicella zoster virus (VZV) has been demonstrated to infect guinea pig enteric neurons in vitro. Latent infection of isolated enteric neurons is established when the cultures predominantly consist of neurons and they are exposed to cell-free VZV. Neurons harboring latent infection survive for weeks in vitro and express mRNA encoding ORFs 4, 21, 29, 40, 62, and 63, but not 14(gC) or 68 (gE) (although DNA encoding the glycoproteins is present). The expressed proteins are the same as those that are also expressed in human sensory neurons harboring latent VZV. In addition to mRNA, the immunoreactivities of ORFs 4, 21, 29, 62, and 63 can be detected. ORF 62 and 29 proteins are cytoplasmic and not intranuclear. VZV does not preferentially infect and/or become latent in intrinsic enteric primary afferent neurons indicating that the virus is latent in these neurons. Lytic infection occurs when mixed cultures of neurons and non-neuronal cells of the bowel wall are exposed to cell-free VZV or when isolated enteric neurons are exposed to cell-associated VZV. When lytic infection occurs, enteric neurons die within 48 hr. Prior to their death, neurons express VZV glycoproteins, including gE and gB, and ORF 62 and 29 proteins are intranuclear. This new animal model should facilitate studies of VZV latency and the efficacy of therapies designed to prevent VZV infection, latency, and reactivation.

Animals↗