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S E Straus

Publications and source records attributed to S E Straus.

At least 127 records · Page 7Linked to original sources
PubMed1995

Analysis of the promoter and cis-acting elements regulating expression of herpes simplex virus type 2 latency-associated transcripts.

In latently infected neurons, herpes simplex virus type 2 (HSV-2) expresses one abundant family of transcripts, the latency-associated transcripts (LATs). We demonstrate here that the sequence lying about 700 bp upstream of the 5' end of the HSV-2 major LAT acts as a very strong promoter in transient expression assays in both neuronal and nonneuronal cells. Transcription starts about 27 to 32 bp downstream of a functional TATA box. The proximal fragment from -102 to +34 includes the basal promoter and accounts for constitutive transcriptional activity in various cell lines. The distal region from -392 to -103 contributes to particularly strong promoter activity in neuronal cell lines and involves multiple cis-acting elements. A functional activating transcription factor/cyclic AMP (cAMP) response element binding protein motif lies just upstream of the TATA. By DNase I footprint and methylation protection assays, we identified several additional protein-binding sites upstream of the activating transcription factor/cAMP response element binding protein motif. A GC-rich element, termed LAT-3, was located between bases -128 to -102. A 2-bp substitution in LAT-3 markedly reduced promoter activity and abolished protein-binding ability in vitro. Gel retardation assay showed no competition for protein binding to LAT-3 by other GC-rich elements. LAT-3 appears to be a novel cis-acting element that may contribute to the neuronal responsiveness of the HSV-2 LAT promoter.

Animals↗
PubMed1995

Interactions between varicella-zoster virus IE62 and cellular transcription factor USF in the coordinate activation of genes 28 and 29.

Varicella-zoster virus (VZV) gene 28 encodes the viral DNA polymerase, while 29 encodes the major DNA-binding protein. Because of the central importance of these proteins to productive replication of VZV and because, of these, only gene 29 seems to be expressed in latency, we sought to understand how their expression is controlled. We recently reported that the divergent gene 28 and gene 29 transcripts are coordinately upregulated by IE62. Deletions in the 221-bp promoter domain shared by genes 28 and 29 comparably diminish the expression of both genes. By a variety of transient expression, competition gel shift, and super-shift assays, we now show that cellular transcription factor USF binds to a palindromic recognition sequence lying equidistant from transcription start sites for both genes 28 and 29. In the presence of IE62, USF fully activates transcription of genes 28 and 29. Site-specific mutation of three bases in the USF core binding hexamer abrogates activation of the gene 28 and 29 promoters by IE62. USF is important for expression of genes 28 and 29 in productive VZV infection.

Base Sequence↗
PubMed1994

The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group.

The complexities of the chronic fatigue syndrome and the methodologic problems associated with its study indicate the need for a comprehensive, systematic, and integrated approach to the evaluation, classification, and study of persons with this condition and other fatiguing illnesses. We propose a conceptual framework and a set of guidelines that provide such an approach. Our guidelines include recommendations for the clinical evaluation of fatigued persons, a revised case definition of the chronic fatigue syndrome, and a strategy for subgrouping fatigued persons in formal investigations.

Fatigue Syndrome, Chronic↗
PubMed1994

Placebo-controlled trial of vaccination with recombinant glycoprotein D of herpes simplex virus type 2 for immunotherapy of genital herpes.

Immunotherapy of chronic viral diseases with vaccines is an important but unproven concept. We investigated the effect of a vaccine containing recombinant glycoprotein D (gD2) of herpes simplex virus type 2 (HSV-2) on the frequency of symptomatic outbreaks in patients with genital herpes. 98 patients with documented genital herpes who reported 4-14 recurrences per year were enrolled in a double-blind, placebo-controlled trial. Subjects received injections of either 100 micrograms gD2 in alum or alum alone (placebo) at 0 and 2 months, and recurrences were documented for 1 year. The vaccine was well tolerated. gD2 recipients reported fewer recurrences per month than placebo recipients (mean 0.42 [SE 0.05] vs 0.55 [0.05]; p = 0.055), had fewer virologically confirmed recurrences per month (0.18 [0.03] vs 0.28 [0.03]; p = 0.019), and had a lower median number of recurrences for the study year (4 [range 0-17] vs 6 [0-15]; p = 0.039). Neither genital recurrence nor the placebo vaccine had any discernible effect on HSV-2-specific antibody responses, but gD2 vaccine boosted neutralising antibodies to HSV-2 fourfold and gD2-specific titres sevenfold over baseline levels. These results inspire optimism about the potential use of vaccine for the treatment of chronic, recurring viral diseases.

Adult↗
PubMed1994

Overview: the biology of varicella-zoster virus infection.

Varicella-zoster virus infection is manifested initially as chickenpox. The virus persists for life in sensory nerve ganglia, from which it reactivates in many people to cause zoster. Among the many recognized complications of these infections, post-zoster neuralgia is the most frequently debilitating. The molecular events of virus replication, latency, and reactivation, and the pathogenesis of post-zoster neuralgia, are incompletely understood and inadequately addressed by current therapeutic strategies.

Female↗
PubMed1994

Varicella-zoster virus (VZV) virion-associated transactivator open reading frame 62 protein enhances the infectivity of VZV DNA.

Varicella-zoster virus (VZV) open reading frame (ORF) 62 protein (the homolog of herpes simplex virus type 1 (HSV-1) ICP4) and ORF10 protein (the homolog of HSV-1 VP16) are virion-associated transactivators. To investigate whether these proteins function during the initial stages of VZV infection, human melanoma cells were cotransfected with purified VZV DNA, devoid of any structural proteins, along with a plasmid expressing VZV ORF62 or ORF10 under the control of the human cytomegalovirus major immediate-early promoter. Expression of ORF62 enhanced the infectivity of VZV DNA up to 70-fold. In contrast, expression of ORF10 enhanced the infectivity of VZV DNA only threefold. These results show that high-level expression of ORF62 protein increases the probability that transfected VZV DNA will result in productive infection, suggesting that this virion-associated transactivator (ORF62) has a critical role in initiating infection.

Base Sequence↗
PubMed1994

Down-regulation of glial fibrillary acidic protein expression during acute lytic varicella-zoster virus infection of cultured human astrocytes.

The effects of the varicella-zoster virus (VZV) OKA vaccine strain in producing morphologic and antigenic changes in dissociated cultures of human fetal brain was investigated. Cultures containing 80% glial acidic fibrillary protein (GFAP), GFAP+ (positive) astrocytes and 20% GFAP- (negative) fibroblastic-like cells were infected with cell-free VZV OKA at a multiplicity of infection of 0.1 plaque-forming units per cell. Cytopathic effects and significant viral antigen labeling with antibodies against VZV gpl and immediate-early (IE) protein 62 were first detected 6 to 7 days postinfection. Several observations indicated that astrocyte GFAP expression was altered and diminished as a result of VZV infection itself, thereby raising doubts about the utility of combining cell markers and viral antigenic labeling in assessing the susceptibility of neural cell types to viral infection. The down-regulation of GFAP expression by VZV appears to be mediated by early rather than late events in the viral replication cycle and may not be the result of virally induced global shut-off of host cell protein synthesis. Similar observations were made using VZV Ellen, a multipassaged, nonvaccine strain. These observations have potential in vivo implications related to histologic analysis of VZV-infected tissues and disease pathogenesis.

Astrocytes↗
PubMed1994

Quantity of latency-associated transcript produced by herpes simplex virus is not predictive of the frequency of experimental recurrent genital herpes.

The role of the latency-associated transcript (LAT) in control of recurrent herpes simplex virus type 2 (HSV-2) infection was investigated by examining whether LAT concentration in vitro during productive infection or in ganglia during latency correlated with frequency of recurrent genital herpes. Clinical HSV-2 isolates from frequent or infrequent recurrent genital disease produced comparable amounts of glycoprotein D and infected cell polypeptide 0 RNA, but the isolate from frequent disease produced about seven times more LAT. The guinea pig model of genital herpes was used to determine whether the quantity of LAT produced during acute infection in vitro correlated with recurrence phenotype; the frequency of recurrent disease was similar for the 2 clinical isolates. Likewise, there was no correlation between the recurrence phenotype of individual animals and LAT concentration in their ganglia. Thus, while absence of LAT may impair HSV reactivation and recurrence, once a threshold concentration is exceeded, LAT has no further effect on recurrence frequency.

Adult↗
PubMed1994

Chronic fatigue syndrome: point and counterpoint.

Two clinical investigators with divergent views on chronic fatigue syndrome (CFS) were invited to debate their positions at the 1993 annual meeting of The Infectious Disease Society of America. Major points of the discourse focused on the value of the US Centers for Disease Control and Prevention case definition of CFS, the potential roles of infectious and allergic problems in the syndrome, the confounding problem of concurrent psychiatric problems, and the utility of diagnostic tests.

Fatigue Syndrome, Chronic↗
PubMed1994

A novel latency-active promoter is contained within the herpes simplex virus type 1 UL flanking repeats.

Herpes simplex virus type 1 (HSV-1) expresses a unique series of RNA molecules, the latency-associated transcripts or LATs, during latent infection of neuronal tissues. Previous studies by others have described a TATA box-containing latency-active promoter, referred to here as LAP1, located approximately 700 bp upstream of the 5' end of the major 2.0-kb LAT. In this report, transient gene expression assays were employed to identify a second, novel latency-active promoter (LAP2) present within a region downstream of LAP1 and 5' proximal to the major 2.0-kb LAT. In contrast to LAP1, this promoter lacks a TATA box but possesses cis-acting regulatory elements and other features frequently observed within eukaryotic housekeeping gene promoters. Unlike most other HSV promoters, LAP2 was down-regulated by the viral transcriptional activators ICP4 and ICP0. The majority of LAP2-positive regulatory elements were located within sequences from -257 to -58 relative to the 5' end of the 2.0-kb LAT, and the basal promoter mapped within sequences from -14 to +28. RNase protection experiments demonstrated that chimeric LAT-chloramphenicol acetyltransferase transcripts produced in the transient assays initiated at or near the 5' end of the major 2-kb LAT. Tn5 insertional mutagenesis of the ICP4 regulatory gene determined that down-regulation of LAP2 required the ICP4 transactivating domain and targeted the minimal promoter region as the site of action by ICP4. Replicating recombinant viruses containing a LAP2-lacZ reporter gene cassette in an ectopic site (glycoprotein C locus) were shown to be active in mouse trigeminal ganglia. Taken together, these experiments suggest that the LAT region of the HSV-1 genome contains at least two latency-active promoters which may play different roles in expressing the various LATs. Alternatively, these promoters may comprise a larger promoter-regulatory complex which may influence transcription during latency.

Animals↗
PubMed1994

Varicella-zoster virus open reading frame 4 encodes a transcriptional activator that is functionally distinct from that of herpes simplex virus homology ICP27.

Varicella-zoster virus is the etiological agent of chickenpox and zoster in humans and belongs to the Alphaherpesvirinae subfamily within the family Herpesviridae. Much of the current understanding of gene regulation in alphaherpesviruses has been derived from studies of the prototype herpes simplex virus (HSV). In HSV, two virus-encoded, trans-regulatory proteins, ICP4 and ICP27, are essential for the replicative cycle of the virus. ICP4 is important in modulating HSV genes of all three kinetic classes, whereas the trans-regulatory effects of ICP27 are primarily associated with the expression of late genes. Recent evidence indicates that the trans-regulatory effects of ICP27 involve posttranscriptional processing of target gene transcripts (R. M. Sandri-Golding and G. E. Mendoza, Genes Dev. 6:848-863, 1992). The ICP27 homolog in varicella-zoster virus is a 452-amino-acid polypeptide encoded by the open reading frame 4 (ORF4) gene. Contrary to what is found with ICP27, we show that the ORF4 polypeptide is a transcriptional activator of diverse target promoters and has a critical requirement for the presence of upstream elements within these promoters to mediate its transcriptional effects. Evidence is also presented to implicate a critical role for the cysteine-rich, C-terminal region of the ORF4 polypeptide in its trans-regulatory functions. Specifically, by oligonucleotide-directed site-specific mutagenesis, we demonstrate that of 10 cysteine residues in the ORF4 polypeptide, only C-421 and C-426 are essential for transactivator function and suggest that these cysteine residues may participate in critical protein-protein interactions rather than protein-nucleic acid interactions to mediate ORF4 inducibility.

Base Sequence↗
PubMed1994

The cellular transcription factor USF cooperates with varicella-zoster virus immediate-early protein 62 to symmetrically activate a bidirectional viral promoter.

The mechanisms governing the function of cellular USF and herpesvirus immediate-early transcription factors are subjects of considerable interest. In this regard, we identified a novel form of coordinate gene regulation involving a cooperative interplay between cellular USF and the varicella-zoster virus immediate-early protein 62 (IE 62). A single USF-binding site defines the potential level of IE 62-dependent activation of a bidirectional viral early promoter of the DNA polymerase and major DNA-binding protein genes. We also report a dominant negative USF-2 mutant lacking the DNA-binding domain that permits the delineation of the biological role of both USF-1 and USF-2 in this activation process. The symmetrical stimulation of the bidirectional viral promoter by IE 62 is achieved at concentrations of USF-1 (43 kDa) or USF-2 (44 kDa) already existing in cells. Our observations support the notion that cellular USF can intervene in and possibly target promoters for activation by a herpesvirus immediate-early protein.

Base Sequence↗
PubMed1993

Oral acyclovir to suppress frequently recurrent herpes labialis. A double-blind, placebo-controlled trial.

OBJECTIVE: To determine whether oral acyclovir reduces the incidence of recurrent herpes labialis in otherwise healthy patients with proven frequently recurrent disease. DESIGN: Randomized, double-blind, placebo-controlled, crossover trial. SETTING: Outpatient facility of the Clinical Center, National Institutes of Health, Bethesda, Maryland. PATIENTS: Fifty-six otherwise healthy adults who reported frequently recurrent herpes labialis (> or = 6 episodes/y) were enrolled into the study. During a 4-month observation period, 22 patients had herpes labialis two or more times and were eligible for study treatment. INTERVENTIONS: Twenty-two patients were randomized to receive either acyclovir, 400 mg twice daily, or matched placebo for 4 months. After the first treatment period, patients were given the alternate treatment for another 4 months and were then taken off study medication to observe the first post-treatment recurrence. Recurrent outbreaks were determined by examination and by viral culture. RESULTS: Twenty patients completed blind treatment with both acyclovir and placebo. The median time to first clinically documented recurrence was 46 days for placebo courses and 118 days for acyclovir courses (P = 0.05). The mean number of recurrences per 4-month treatment period was 1.80 episodes per patient during placebo treatment and 0.85 episodes per patient during acyclovir treatment (P = 0.009). The mean number of virologically confirmed recurrences per patient was 1.40 with placebo therapy compared with 0.40 with acyclovir (P = 0.003). CONCLUSIONS: Oral acyclovir, 400 mg twice daily, is effective in suppressing herpes labialis in immunocompetent adults confirmed to have frequently recurrent infection. Treatment with acyclovir in this study resulted in a 53% reduction in the number of clinical recurrences and a 71% reduction in virus culture-positive recurrences compared with placebo therapy.

Acyclovir↗
PubMed1993

NIH conference. Epstein-Barr virus infections: biology, pathogenesis, and management.

Epstein-Barr virus (EBV) encodes genes that ensure its persistence in human B lymphocytes. Some of the genes encourage B-cell proliferation; others are poised to evade or defeat immune recognition. Immune restraints on the virus, however, are typically so effective that most infections are never symptomatic. In contrast, acute infectious mononucleosis, a self-limited lymphoproliferative illness, is common in adolescents and young adults. Unbridled proliferative illnesses arise when cellular immunity is grossly defective. Treatment of EBV-associated syndromes is largely supportive. Antiviral drugs have no proven role except in patients with oral hairy leukoplakia. Vaccine development is technically feasible but is not considered a high priority for developed nations.

B-Lymphocytes↗