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At least 37 records · Page 2Linked to original sources
PubMed2004

Role of NF-kappa B in cell survival and transcription of latent membrane protein 1-expressing or Epstein-Barr virus latency III-infected cells.

Epstein-Barr virus (EBV) latency III infection converts B lymphocytes into lymphoblastoid cell lines (LCLs) by expressing EBV nuclear and membrane proteins, EBNAs, and latent membrane proteins (LMPs), which regulate transcription through Notch and tumor necrosis factor receptor pathways. The role of NF-kappa B in LMP1 and overall EBV latency III transcriptional effects was investigated by treating LCLs with BAY11-7082 (BAY11). BAY11 rapidly and irreversibly inhibited NF-kappa B, decreased mitochondrial membrane potential, induced apoptosis, and altered LCL gene expression. BAY11 effects were similar to those of an NF-kappa B inhibitor, Delta N-I kappa B alpha, in effecting decreased JNK1 expression and in microarray analyses. More than 80% of array elements that decreased with Delta N-I kappa B alpha expression decreased with BAY11 treatment. Newly identified NF-kappa B-induced, LMP1-induced, and EBV-induced genes included pleckstrin, Jun-B, c-FLIP, CIP4, and I kappa B epsilon. Of 776 significantly changed array elements, 134 were fourfold upregulated in EBV latency III, and 74 were fourfold upregulated with LMP1 expression alone, whereas only 28 were more than fourfold downregulated by EBV latency III. EBV latency III-regulated gene products mediate cell migration (EBI2, CCR7, RGS1, RANTES, MIP1 alpha, MIP1 beta, CXCR5, and RGS13), antigen presentation (major histocompatibility complex proteins and JAW1), mitogen-activated protein kinase pathway (DUSP5 and p62Dok), and interferon (IFN) signaling (IFN-gamma R alpha, IRF-4, and STAT1). Comparison of EBV latency III LCL gene expression to immunoglobulin M (IgM)-stimulated B cells, germinal-center B cells, and germinal-center-derived lymphomas clustered LCLs with IgM-stimulated B cells separately from germinal-center cells or germinal-center lymphoma cells. Expression of IRF-2, AIM1, ASK1, SNF2L2, and components of IFN signaling pathways further distinguished EBV latency III-infected B cells from IgM-stimulated or germinal-center B cells.

Apoptosis↗
PubMed1997

IRF-7, a new interferon regulatory factor associated with Epstein-Barr virus latency.

The Epstein-Barr virus (EBV) BamHI Q promoter (Qp) is the only promoter used for the transcription of Epstein-Barr virus nuclear antigen 1 (EBNA-1) mRNA in cells in the most restricted (type I) latent infection state. However, Qp is inactive in type III latency. With the use of the yeast one-hybrid system, a new cellular gene has been identified that encodes proteins which bind to sequence in Qp. The deduced amino acid sequence of the gene has significant homology to the interferon regulatory factors (IRFs). This new gene and products including two splicing variants are designated IRF-7A, IRF-7B, and IRF-7C. The expression of IRF-7 is predominantly in spleen, thymus, and peripheral blood leukocytes (PBL). IRF-7 proteins were identified in primary PBL with specific antiserum against IRF-7B protein. IRF-7s can bind to interferon-stimulated response element (ISRE) sequence and repress transcriptional activation by both interferon and IRF-1. Additionally, a functional viral ISRE sequence, 5'-GCGAAAACGAAAGT-3', has been identified in Qp. Finally, the expression of IRF-7 is consistently high in type III latency cells and almost undetectable in type I latency, corresponding to the activity of endogenous Qp in these latency states and the ability of the IRF-7 proteins to repress Qp-reporter constructs. The identification of a functional viral ISRE and association of IRF-7 with type III latency may be relevant to the mechanism of regulation of Qp.

Amino Acid Sequence↗
PubMed1990

Biological and molecular aspects on herpes simplex virus latency.

Latent reactivateable herpes simplex virus (HSV) infections of sensory neurons of peripheral ganglia are most plausibly the source of clinical herpetic recurrences. The establishment of latency is the result of a concert of both viral and cellular factors such as the neuroinvasiveness of the virus, the relative density of receptors binding virus to the nerve cell plasma membrane, the permissiveness of the infection, including the axonal transport of the viral nucleocapsids, and the restriction of virus replication. Several hypotheses have been presented suggesting various mechanisms for the restriction of the HSV infection of the neuron. Thus, for instance the the importance of thymidine kinase negative mutants, hypermethylation of viral DNA and the existence of latency-associated viral genes have been discussed. Activation of the latent infection to a virus-producing lytic infection by means of superinfection with a replication-incompetent mutant is probably a result of genetic complementation. Reactivation by means of superinfection with replication-competent virus seems dependent upon the multiplicity of the superinfecting virus and more than one copy of the virus genome is required for the initiation of the reactivating process. These observations would be consistent with the overcoming of a cellularly controlled restriction of the latent infection. The cellular control of latency which can be impaired mechanically and chemically seems particularly important for the maintenance of latent HSV infection. However, recent observations indicate that reactivation of latent HSV infection is also associated with the expression of a latency-related viral gene (LAT), whereas establishment of the latency apparently is influenced by other properties determined by the genome of the virus, as well as by the capacity of the cell to restrict the lytic infection.

Ganglia↗
PubMed1999

2'-Deoxy-5-ethyl-beta-4'-thiouridine inhibits replication of murine gammaherpesvirus and delays the onset of virus latency.

The antiviral thionucleoside analogue 2'-deoxy-5-ethyl-beta-4'-thiouridine (4'-S-EtdU) was shown to be a more potent inhibitor of gammaherpesvirus infection than acyclovir. This compound inhibits replication of murine herpesvirus (MHV)-68 in the lungs of mice when given 3 days post-infection. However, as with other nucleoside analogues, it was unable to prevent the establishment of latency, despite delaying the onset of latent infection in the spleen. In contrast, virus persistence in the lung was inhibited following drug treatment, although persistence was re-established in mice when treatment was suspended after 12 days. These data suggest that 4'-S-EtdU is a highly effective inhibitor of murine gammaherpesvirus replication and as such provides a powerful tool to study the pathogenesis of this virus in vivo.

Animals↗
PubMed1995

HSV-1 brain infection by the olfactory nerve route and virus latency and reactivation may cause learning and behavioral deficiencies and violence in children and adults: a point of view.

Two recent studies provided new evidence on the latency of HSV-1 DNA in 15.5% of olfactory bulbs and in 72.5% of trigeminal nerves from human corpses at forensic postmortems (1) and in 35% of 40 autopsied human brains (2). In the latter brains, latent HSV-1 DNA was found in the olfactory bulbs, amygdala, hippocampus, brain stem, and trigeminal ganglia. Although in these studies it is not known by which route HSV-1 entered the olfactory bulbs and brain, experimental studies in mice (3) revealed that injection of HSV-1 into the olfactory bulbs leads to virus migration into the brain amygdala and hippocampus via the olfactory nerve and locus coeruleus. If the olfactory ciliary nerve epithelium is the port of entry of HSV-1 into the olfactory bulbs and brain in humans as well, protection of the nose against HSV-1 infection may be needed to prevent virus latency in neurons in the amygdala and hippocampus (3). Infection of humans by HSV-1 was estimated to increase from 18.2% in the 0-20 year population group to 100% in persons older than 60 years (1), indicating that worldwide human populations at all ages are at risk of brain infection by the olfactory nerve route. In addition, both primary infection and reactivation of latent DNA in the brain may lead to damage of neurons in the brain involved in memory, learning, and behavior, as observed in infected, acyclovir-treated mice (3). The current introduction of a live apathogenic varicella-zoster virus (VZV) vaccine to immunize children against chickenpox (4) may suggest that the time is ripe for immunization of children and adults against HSV-1 infections, especially infections by the olfactory nerve route, to prevent potential brain damage.

Adult↗
PubMed1993

A mouse model for varicella-zoster virus latency.

Following primary infection with varicella-zoster virus (VZV), the virus establishes a latent infection in humans. The molecular pathogenesis of VZV latency is not well understood, mainly due to the lack of an adequate animal model. We report here that we have developed a mouse model for VZV infection that involves corneal inoculation of mice. Although infected animals showed no signs of disease, most of the animals could not eliminate the virus early after infection. By PCR, we demonstrated that at 33 days post-infection (p.i.), viral DNA was still present in more than 60% of the animals (14/21). VZV DNA was most frequently detected in the trigeminal ganglia (7/14) followed by the brain stem (10/21), kidneys (4/21), spleen (3/20), liver (2/21) and brain (1/21). By in situ hybridization, a few cells positive for VZV mRNA were detected in the trigeminal ganglia, brain stem, cerebellum and spleen of a small number of the infected animals as late as 33 days p.i. No viral proteins were detected at the site of inoculation or in any other tissue by immunostaining. Our results suggest that VZV spreads in mice by both viraemia and axonal transport and establishes a non-productive (latent) infection.

Animals↗
PubMed2000

Epstein-Barr virus latency: LMP2, a regulator or means for Epstein-Barr virus persistence?

Like other herpesviruses, Epstein-Barr virus (EBV) persists in its host through an ability to establish a latent infection that periodically reactivates, producing infectious virus that infects naïve hosts. Disease syndromes in humans caused by EBV reflect the cell types that EBV infects, being primarily of lymphoid or epithelial origin. The most notable lymphoid disease, infectious mononucleosis, is a self-limiting lymphoproliferative disease that occurs in normal adolescents on primary infection. Children are normally able to resolve primary EBV infection with few or no symptoms. By the age of 25 most individuals are EBV seropositive. EBV is associated with a variety of hematopoietic cancers such as African Burkitt's lymphoma, Hodgkin's, and adult T-cell leukemia. EBV-associated lymphoproliferative disease occurs in individuals with congenital or acquired cellular immune deficiencies. The two notable epithelial diseases associated with EBV infection are nasopharyngeal cancer, a malignancy endemic to southern China, and oral hairy leukoplakia, an epithelial hyperplasia of the lingual squamous epithelium in AIDS patients. Latent membrane protein 2 (LMP2) is expressed both in normal EBV latency and EBV-associated pathologies. LMP2 may regulate reactivation from latency by interfering with normal B-cell signal transduction processes and in doing so may also provide a survival signal that could be important for viral persistence. Current knowledge about the function of LMP2 is described, defining a new class of regulators of herpesvirus latency.

Adolescent↗
PubMed2005

Towards an understanding of the molecular basis of herpes simplex virus latency.

The survival strategy of herpes simplex virus centres on the establishment of latency in sensory neurons innervating the site of primary infection followed by periodic reactivation to facilitate transmission. This is a highly evolved and efficient survival mechanism, which despite being the subject of intense research, has proven remarkably difficult to dissect at a molecular level. This review will focus on data, emerging from both in vitro and in vivo model systems, which provide a framework for a mechanistic understanding of latency and the existence and possible significance of non-uniform latent states.

Animals↗
PubMedDate not supplied

Varicella-zoster virus latency in human ganglia.

Varicella-zoster virus (VZV) is a human herpesvirus which causes varicella (chickenpox) as a primary infection, and, following a variable period during which it remains in latent form in trigeminal and dorsal root ganglia, reactivates in later life to cause herpes zoster (shingles). VZV is a significant cause of neurological disease including post-herpetic neuralgia which may be persistent and highly resistant to treatment, and small and large vessel encephalitis. VZV infections are more frequent with advancing age and in immunocompromised individuals. An understanding of the mechanisms of latency is crucial in developing effective therapies for VZV infections of the nervous system. Such studies have been hampered by the difficulties in working with the virus and also the lack of a good animal model of VZV latency. It is known that the ganglionic VZV burden during latency is low. Two of the key questions that have been addressed are the cellular site of latent VZV and the identity of the viral genes which are transcribed during latency. There is now a consensus that latent VZV resides predominantly in ganglionic neurons with less frequent infection of non-neuronal satellite cells. There is considerable evidence to show that at least five viral genes are transcribed during latency. Unlike herpes simplex virus-1 latency, viral protein expression has been demonstrated during VZV latency. A precise knowledge of which viral genes are expressed is crucial in devising novel antiviral therapy using expressed genes as therapeutic targets. Whether gene expression at both the transcriptional and translational levels is more extensive than currently reported will require much more work and probably new molecular technology.

Chickenpox↗
PubMed2002

Spontaneous mobilization of integrated recombinant adenoassociated virus in a cell culture model of virus latency.

A cell line containing integrated recombinant adenoassociated virus (AAV) was investigated for spontaneous mobilization of vector sequence. Detection of these rare events was facilitated by using a vector design that allowed the circular rescue product (cAAV) to be individually scored by bacterial transformation. Restriction and sequence analysis of captured clones revealed five highly ordered classes of cAAV, each of which contained a defined segment of the integrated vector locus. A common feature of all cAAV classes was the presence of a modified inverted terminal repeat that joined the ends of the liberated sequence. Assembly of extrachromosomal vector genomes was accompanied by deletions in the integration locus that could be mapped to one of the five cAAV classes, suggesting an excision-type mechanism. We propose that the spontaneous deletion and mobilization of vector sequence from the recombinant adenoassociated virus (rAAV) integration locus is mediated by a recombination event between the inverted terminal repeats that define the boundaries of the individual genome subunits.

Cell Line↗
PubMed1994

Correlation between precolonization of trigeminal ganglia by attenuated strains of pseudorabies virus and resistance to wild-type virus latency.

We compared the levels of latent pseudorabies virus (PRV) DNA in trigeminal ganglia (TG) of pigs after intranasal inoculation of different PRV strains by using quantitative DNA PCR. The extent of colonization attained in each case varied significantly according to the type of strain and inoculum dose, wild-type (WT) PRV being the most efficient strain in colonizing TG. When groups of pigs representing different levels of precolonization of TG with an attenuated PRV strain were challenged with WT PRV, it became evident that there is a statistically significant inverse correlation between the extent of precolonization attained by an attenuated PRV strain in TG and the level of establishment of latency by superinfecting WT PRV. The protection against WT PRV latency did not correlate with the extent of WT PRV replication at the portal of entry.

Analysis of Variance↗
PubMed2000

Induction of circular episomes during rescue and replication of adeno-associated virus in experimental models of virus latency.

The synthesis of linear duplex replicative structures (monomers, head-to-head, and tail-to-tail dimers) is an important hallmark of the productive phase of the adeno-associated virus (AAV) life cycle. These structures are generated by a strand-displacement replication mechanism and believed to be a reservoir for single-stranded DNA genomes. During the course of studies with recombinant versions of AAV (rAAV), we discovered the assembly of circular duplex provirus derivatives in latently infected cell lines under conditions permissive for replication (i.e., helper virus dependent). These novel structures were cloned by bacterial trapping revealing a markedly homogeneous structure that included a single copy of the rAAV genome joined head-to-tail about the inverted terminal repeats (ITR). Restriction and sequence analysis of the point of circularization revealed a so-called "TRT" domain, consisting of a single ITR hairpin palindrome flanked by 5' and 3' D sequence elements. The circular conformation was additionally characterized by Southern blotting and confirmed by purification on an ethidium bromide-CsCl gradient where the buoyant density was consistent with circular supercoiled DNA. These findings suggest that AAV replication is accompanied by the assembly of circular duplex structures.

Blotting, Southern↗
PubMed1990

Pseudorabies virus latency: restricted transcription.

Cloned pseudorabies virus (PRV) sequences representing over 80% of the viral genome were radiolabeled and individually hybridized to nucleic acid in the trigeminal ganglia of acutely and latently infected swine. In acutely infected animals, all cloned probes hybridized to PRV RNA and DNA. In contrast, during latency transcription was found to be limited to a selected region, corresponding to the IE gene, analogous to that of two other alpha-herpesviruses. Viral DNA was not detected in latently infected neurons by in situ hybridization.

Animals↗
PubMed1994

Herpes simplex virus latency in tissue culture cells.

We have developed tissue culture systems which mimic certain aspects of herpes simplex virus (HSV) latency, in order to facilitate molecular studies of the phenomenon. The initial approach utilised incubation at 42 degrees C to suppress virus replication and establish stable latency after infection of human fibroblasts at low multiplicity with HSV-2. Latent virus was reactivated efficiently by superinfection of cultures with HSV-1 or human cytomegalovirus. Improvement of the system was achieved by use of the HSV-1 mutant in1814, which has a 12 base pair insertion in the coding sequences for the transactivating protein Vmw65 (VP16). Upon infection with in1814 at 42 degrees, or 37 degrees, it was possible to obtain cultures in which up to 21% of cells contained a viral genome. More recent modifications include the use of mutant in1820 (a derivative of in 1814) and pretreatment of cells with interferon alpha, which enable latency to be established in approximately 100% of cells. A system has therefore been developed that is suitable for the analysis of gene expression and genome structure during latency and reactivation.

Cells, Cultured↗
PubMed1996

CpG methylation of the major Epstein-Barr virus latency promoter in Burkitt's lymphoma and Hodgkin's disease.

The Epstein-Barr virus (EBV) latency C promoter drives expression of a family of viral proteins commonly targeted by CD8 cytotoxic T cells. These proteins are not generally expressed in African Burkitt's lymphoma and in EBV-associated Hodgkin's disease. The failure to express these proteins is almost certainly an important factor in the evasion of immunosurveillance by EBV-associated tumors. In a previous study, we have shown that transcriptional activation of the C promoter is inhibited by methylation of a particular CpG site upstream of the promoter that prevents binding of a cellular protein (CBF2), and we have shown that this and adjacent CpG sites are methylated in a Burkitt's lymphoma cell line. In the present study, we show that CpG sites in the CBF2 binding region are predominantly methylated in African Burkitt's lymphoma and in EBV-associated Hodgkin's disease. In addition, we present the first direct evidence that the C promoter is transcriptionally silent in Burkitt's lymphoma. In contrast, we show a complete absence of methylation in the CBF2 binding region in a case of reversible EBV-associated B-cell lymphoma arising in an immunocompromised patient whose tumor shows C promoter transcriptional activity. By inhibiting expression of highly antigenic viral proteins, methylation of transcriptional control sequences may veil the presence of virus in tumor tissue from CD8(+) cytotoxic T-cell immune surveillance and thus facilitate viral tumorigenesis.

5-Methylcytosine↗
PubMed1989

Transcriptional activity of the herpes simplex virus genome during establishment, maintenance, and reactivation of in vitro virus latency.

We previously have described a model of in vitro herpes simplex virus (HSV) latency in which latent infection was (i) established with human leukocyte interferon (IFN-alpha) in combination with (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) or 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir); (ii) maintained after termination of combined inhibitor treatment by incubation at 40.5 degrees, and (iii) reactivated by either reducing the incubation temperature to 37 degrees or by superinfecting at the elevated temperature with human cytomegalovirus (HCMV). We now report the use of this system to examine the transcriptional activity of the HSV genome during establishment, maintenance, and reactivation of HSV latency in vitro. Numerous species of virus-specific polyadenylated RNAs were present during the first 3 days of combined BVDU and IFN-alpha treatment of HSV type 1 (HSV-1)-infected human fetus lung fibroblast cells. However, after 7 days of combined inhibitor treatment, only a very small quantity of virus-specific RNA could be detected utilizing the short unique region of the HSV-1 genome as probe. After terminating combined BVDU and IFN-alpha treatment and increasing the temperature from 37 to 40.5 degrees on day 7 after infection, virus-specific RNA was undetectable by RNA blot hybridization analysis; however, a small amount of HSV-specific RNA was detected in 2% of the cells by in situ hybridization. The HSV-1 transcriptional products produced after HCMV superinfection in the presence of selected inhibitors of macromolecular synthesis also were examined and demonstrated that the efficient activation of HSV-1 immediate-early gene transcription required the expression of not only immediate-early HCMV gene product(s), but also at least a subset of early-late gene products.

Blotting, Northern↗
PubMed2003

Herpes simplex virus-1 and varicella-zoster virus latency in ganglia.

Two human alpha-herpesviruses, herpes simplex virus (HSV)-1 and varicella zoster virus (VZV), account for the most frequent and serious neurologic disease caused by any of the eight human herpesviruses. Both HSV-1 and VZV become latent in ganglia. In this review, the authors describe features of latency for these viruses, such as distribution, prevalence, abundance, and configuration of viral DNA in latently infected human ganglia, as well as transcription, translation, and cell type infected. Studies of viral latency in animal models are also discussed. For each virus, remaining questions and future studies to understand the mechanism of latency are discussed with respect to prevention of serious cutaneous, ocular, and neurologic disease produced by virus reactivation.

Animals↗