Gene/Protein Disease Symptom Drug Enzyme Compound
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Several unusual features were observed during routine histopathological confirmation of a clinical diagnosis of Alzheimer's disease (AD) in an 85-year-old, right-handed, married male. The patient presented with a 12-year history of slowly progressive cognitive impairment, which increased in severity just prior to death. Detailed postmortem examination of the frontal lobes revealed a significant number of neuritic plaques and neurofibrillary tangles. Multifocal spongiform encephalopathic changes, mononuclear perivascular infiltrates, subcortical demyelination and gliosis were also found. Of particular interest were well-defined neuronal and astrocytic intranuclear inclusion bodies (Cowdry type I and I), suggestive of viral disease. Electron microscopy, immunohistochemical and immunohistofluorescent studies confirmed a Herpes simplex type I encephalitis (HSV-I). These histological results and the clinical history of progression suggest that reactivation of a latent viral infection may have contributed to the rapid progression of dementia prior to death. The present analysis underscores the fact that multiple etiologic factors may act simultaneously to produce dementia. While one such process may be identified or diagnosed (in the present case AD), it is necessary to be open to the possibility that another mechanism may come into play during the time course of that illness. A differential diagnosis may be difficult when the symptoms of the two disease processes are very similar. Such may be the case if there is reactivation of a previously undiagnosed herpes virus infection. With the development of PCR and in situ hybridization diagnosis will be simplified and more definitive.
Cell Mol Biol (Noisy-le-grand) 2003 Dec
PMID:Coexistence of Alzheimer disease neuropathology with herpes simplex encephalitis. 1498 92

Epstein-Barr Virus (EBV), a ubiquitous gamma herpes virus, infects more than 95% of the human population before adulthood. Life-long persistence, usually without adverse health consequences, relies on a balance between viral latency, viral replication, and host immune response. Patients with EBV-related disease often have high levels of EBV DNA in their plasma. This study addresses whether this circulating, cell-free EBV DNA is encapsidated in virions or exists as naked genomes. First, an assay was developed, combining DNase I and quantitative real-time PCR, to discriminate encapsidated from naked EBV DNA. EBV DNA was almost always naked in the plasma of AIDS-related lymphoma patients (n = 11) and immunosuppressed/posttransplantation patients (n = 8). In contrast, infectious mononucleosis patients (n = 30) often had a mixture of encapsidated and naked EBV DNA. These findings may be important in understanding how viral load relates to disease status and in predicting response to nucleoside analogs and other antiviral therapies.
Diagn Mol Pathol 2004 Jun
PMID:Epstein-Barr Virus (EBV) DNA in plasma is not encapsidated in patients with EBV-related malignancies. 1516 6

The kinetics of Herpes simplex infection development was studied using an FTIR microscopy (FTIR-M) method. The family of herpes viruses includes several members like H. simplex types I and II (HSV I, II), Varicella zoster (VZV) viruses which are involved in various human and animal infections of different parts of the body. In our previous study, we found significant spectral differences between normal uninfected cells in cultures and cells infected with herpes viruses at early stages of the infection. In the present study, cells in cultures were infected with either HSV-I or VZV and at various times post-infection they were examined either by optical microscopy or by advanced FTIR-M. Spectroscopic measurements show a consistent decrease in the intensity of the carbohydrate peak in correlation with the viral infection development, observed by optical microscopy. This decrease in cellular carbohydrate level was used as indicator for herpes viruses infection kinetics. This parameter could be used as a basis for applying a spectroscopic method for the evaluation of herpes virus infection development. Our results show also that the development kinetics of viral infection has an exponential character for these viruses.
Spectrochim Acta A Mol Biomol Spectrosc 2004 Aug
PMID:The use of FTIR microscopy for evaluation of herpes viruses infection development kinetics. 1524 25

DNA microarray technology has become a promising new tool for the detection and identification of viral pathogens in human plasma and cell cultures. For exploration of this technology, we have developed DNA microarrays that encode capture oligonucleotide probes for different human herpes viruses: herpes simplex virus (HSV) HSV-1, HSV-2, varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and HHV-6. The on-chip hybridization is accomplished with the PCR amplicons of the respective human herpes virus types. In this original article, we attached multiple Cy3-fluorophores to the branched 5' ends of the labeling oligonucleotide primers. For the first time, we experimentally demonstrated that the self-designed, knowledge-based, and focused microarrays specifically hybridized to fluorophore-labeled pathogenic DNAs using dendrimer technology. The fluorescence signal enhancement via the dendrimers was up to 30 times compared with the quenched single Cy3-fluorophore-labeled HSV-1 DNA. The on-chip signal-amplifying effect depended upon the number of branches and the concentration of fluorophore-labeled pathogenic DNAs. Treblers were superior to doublers, as trebler-labeled nucleic acids had fluorescence-signal-enhancing effects over a broad range of labeled DNA concentrations exemplified for the quenched single Cy3-fluorophore-labeled HSV-1 and non-quenched single Cy3-fluorophore-labeled CMV DNAs.
Exp Mol Pathol 2004 Oct
PMID:Enhancing sensitivity of human herpes virus diagnosis with DNA microarrays using dendrimers. 1535 Dec 31

Advances in the area of stroke and other neurodegenerative disorders have identified a variety of molecular targets for potential therapeutic intervention. The use of modified viral vectors has now made it possible to introduce foreign DNA into central nervous system cells, permitting overexpression of the protein of interest. A particular advantage of the herpes simplex system is that the herpes virus is neurotropic and is therefore suited for gene therapy to the nervous system. The vectors used by our group to date utilize an amplicon-based bipromoter system, which permits expression of both the gene of interest and a reporter gene. Using this strategy, we have been successful in transferring potentially neuroprotective genes to individual central nervous system cells. Using this approach, it is possible to show that gene therapy both before and after insult is feasible. Some limitations of this technique exist, the main one being delivery and extent of transfection. Although application to clinical stroke is probably remote, viral vector-mediated gene therapy provides a unique and powerful tool in the study of molecular mechanisms involved in brain injury.
Methods Mol Med 2005
PMID:Gene therapy in neurological disease. 1545 65

Herpes simplex virus (HSV), in contrast to most other members of the herpes virus family, has the ability to infect, enter latency, and reactivate from latency in a number of nonhuman species, including mice. This provides a unique opportunity to study the complex lytic-latent cycle of a human neurotropic virus in a mouse model. This chapter details basic methods for inducing and quantifying reactivation, with emphasis on the first strategy for detecting and quantifying the initiation of HSV reactivation in vivo.
Methods Mol Biol 2005
PMID:Detection and quantification of the rare latently infected cell undergoing herpes simplex virus transcriptional activation in the nervous system in vivo. 1550 1

Fourier-transform infrared (FTIR) microscopy is considered a comprehensive and sensitive method for detection of molecular changes in cells. The advantage of FTIR microspectroscopy over conventional FTIR spectroscopy is that it facilitates inspection of restricted regions of a cell culture or a tissue. We have shown that it is possible to apply FTIR microscopy as a sensitive and effective assay for the detection of cells infected with various members of the herpes family of viruses and retroviruses. Detectable and significant spectral differences between normal and infected cells were evident at early stages of the infection. Impressive changes in several spectroscopic parameters were seen in infected compared with uninfected cells. It seems that the change in spectral behavior is specific to the infecting virus, because cells infected with herpesviruses showed different spectral changes compared with cells infected with retroviruses.
Methods Mol Biol 2005
PMID:FTIR microscopy detection of cells infected with viruses. 1550 7

During thymic education, strongly self-reactive T cells are selected against, while weakly self-reactive cells are positively selected. However, the probability of an antigen being self derived and the number of self-peptides have never been properly defined. We merge algorithms for: cleavage prediction, TAP binding probability estimates and MHC binding properties to estimate the number and distribution of all MHC binding peptides. We show that the number of self-peptides with a high affinity to a given human MHC-I molecule is between 200 and almost 200,000 and is much less than the estimated total number of peptide sequences. This result suggests that MHC molecules are selected through evolution in order to reduce the number of self-peptides presented. The number of viral peptides presented is also low and varies between zero and a few hundred per virus for a given HLA allele. These low numbers explain the need for multiple alleles within an individual. We show that six codominantly expressed MHC-I alleles are sufficient to present at least one or two peptides per virus for the vast majority of viruses. Viruses can escape detection either by using peptides that cannot be presented on MHC molecules or by using peptides whose presented segments overlap significantly with self. Most viral families (such as influenza, HIV, Hepatitis and HPV) present as many peptides as predicted from their genome length, and overlap minimally with the human self-peptide repertoire. However, a few latent viruses, such as herpes and adenovirus share considerable peptide sequence homology with their human hosts.
Mol Immunol 2006 Feb
PMID:T-cell epitope repertoire as predicted from human and viral genomes. 1592 55

Varicella-zoster virus (VZV) is a highly species-specific member of the Herpesviridae family. The virus exhibits multiple cell tropisms, infecting peripheral blood mononuclear cells and skin cells before establishing latency in sensory neurons. Such tropisms are essential both for primary infection, which manifests itself as chickenpox (varicella), and subsequent reactivation to cause herpes zoster (shingles). The highly cell-associated nature of the virus, coupled with its narrow host range, has resulted in the lack of an animal model that mimics its diseases in humans, thereby greatly hindering the study of events in VZV pathogenesis. Despite this, extensive studies both in vitro and in vivo in small-animal models have provided a fascinating insight into molecular events that govern VZV diseases. In addition, VZV has become the first human herpes virus for which a live attenuated vaccine has been developed.
Expert Rev Mol Med 2005 Aug 10
PMID:Molecular and therapeutic aspects of varicella-zoster virus infection. 1609 35

The human herpes virus 6 (HHV-6)-encoded chemokine receptor U51 constitutively activates phospholipase C (PLC) and inhibits cAMP-responsive element (CRE)-mediated gene transcription via the activation of G(q/11) proteins. Yet, chemokines known to bind U51 differentially regulate U51 coupling to G proteins. CCL5/RANTES induced pertussis toxin (PTX)-insensitive increases in PLC activity and changes in intracellular free calcium concentration ([Ca2+]i), whereas both CCL2/MCP-1 and CCL11/eotaxin failed to stimulate PLC activity or increase [Ca2+]i. In contrast, all three chemokines counteracted the effects of U51 on CRE activity via the activation of PTX-sensitive G(i/o) proteins. For each of the tested chemokines, coexpression of U51 with a variety of G alpha subunits, however, revealed a distinct profile for preferred G-protein coupling, which could be shifted by modulation of the relative expression of G proteins. These findings are consistent with a chemokine-selective trafficking of receptor stimulus to distinct G proteins and suggest that the constitutive activity of U51 and the chemokine-induced signaling involve different active states of the receptor. By virtue of its ability to constitutively activate signaling pathways, its G-protein promiscuity, and the chemokine-directed trafficking of receptor stimulus, U51 can be considered a sensitive and versatile virally encoded signaling device, potentially of importance in HHV-6-related pathologies.
Mol Pharmacol 2006 Mar
PMID:Chemokine-directed trafficking of receptor stimulus to different g proteins: selective inducible and constitutive signaling by human herpesvirus 6-encoded chemokine receptor U51. 1633 87


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