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See detailDecreased Protein Levels of the C-Cbl Protooncogene in Murine Aids
Trebak, Mohamed; Lambert, Charles A; Rahmouni, Souad ULg et al

in Cellular Immunology (1998), 188(2), 151-7

Murine acquired immunodeficiency syndrome (MAIDS) can be viewed as a lymphoproliferative disease which involves B cells as well as T cells from spleen and lymph nodes while thymus and Peyer's patches do ... [more ▼]

Murine acquired immunodeficiency syndrome (MAIDS) can be viewed as a lymphoproliferative disease which involves B cells as well as T cells from spleen and lymph nodes while thymus and Peyer's patches do not participate in the process. The 120-kDa protooncogene product c-Cbl was initially cloned from the murine Cas NS-1 B cell lymphoma. It is a main target of immunoreceptor (TCR and BCR)-mediated protein tyrosine kinase activity. Moreover, recent data suggest that c-Cbl might play a crucial role in the regulation of cell proliferation through regulation of GTP-binding proteins. Therefore, the involvement of c-Cbl was evaluated in the lymphoproliferative disease induced by the MAIDS virus. The expression of the c-Cbl protein was dramatically reduced in the lymph node of infected mice while it remained normal in the thymus. In contrast, the expression of actin, TCR-zeta chain, ZAP-70, and p59(fyn) remained similar in controls and infected mice. Identical results were obtained with sorted B cells and T cells. Surprisingly, a B cell lymphoma line derived from late stage MAIDS mice displayed a normal level of c-Cbl. [less ▲]

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See detailVaricella-zoster virus open reading frame 4 encodes an immediate-early protein with posttranscriptional regulatory properties
Defechereux, Patricia; Debrus, Serge; Baudoux, Laurence et al

in Journal of Virology (1997), 71(9), 7073-7079

Varicella-zoster virus (VZV) encodes four putative immediate-early proteins based on sequence homology with herpes simplex virus type I: the products of ORF4, -61, -62, and -63. Until now, only two VZV ... [more ▼]

Varicella-zoster virus (VZV) encodes four putative immediate-early proteins based on sequence homology with herpes simplex virus type I: the products of ORF4, -61, -62, and -63. Until now, only two VZV proteins have been described as being truly expressed with immediate-early kinetics (IE62 and IE63). The ORF4-encoded protein can stimulate gene expression either alone or in synergy with the major regulatory protein IE62. Making use of a sequential combination of transcription and protein synthesis inhibitors (actinomycin D and cycloheximide, respectively), we demonstrated the immediate-early nature of the ORF4 gene product, which can thus be named IE4. The fact that IE4 is expressed with kinetics similar to that of IE62 further underlines the possible cooperation between these two VZV proteins in gene expression. Analysis of the IE4-mediated autologous or heterologous viral gene expression at the mRNA levels clearly indicated that IE4 may have several mechanisms of action. Activation of the two VZV genes tested could occur partly by a posttranscriptional mechanism, since increases in chloramphenicol acetyltransferase (CAT) mRNA levels do not account for the stimulation of CAT activity. On the other hand, stimulation of the human immunodeficiency virus type 1 long terminal repeat-or the cytomegalovirus promoter-associated CAT activity is correlated with an increase in the corresponding CAT mRNA. [less ▲]

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See detailRecognition of the latency-associated immediate early protein IE63 of varicella-zoster virus by human memory T-lymphocytes
Sadzot-Delvaux, Catherine ULg; Kinchington, Paul R.; Debrus, Serge et al

in Journal of Immunology (1997), 159(6), 2802-2806

Varicella-zoster virus (VZV) is a human alpha herpesvirus that establishes latency in sensory ganglia. Latency is characterized by the abundant expression of the immediate early protein 63 (IE63), whereas ... [more ▼]

Varicella-zoster virus (VZV) is a human alpha herpesvirus that establishes latency in sensory ganglia. Latency is characterized by the abundant expression of the immediate early protein 63 (IE63), whereas other viral proteins have not yet been detected during the quiescent phase of VZV infection. The IE63 protein is a component of the virion and is expressed very early in the infectious cycle. The IE63 protein is also expressed in skin during episodes of varicella and herpes zoster. We have evaluated the cell-mediated immune response against IE63 in naturally immune adults with a history of chickenpox, by T lymphoproliferation and cytotoxicity assays. Among donors who had T cell proliferation to unfractionated VZV Ags from infected cell extract, 59% had T cell recognition of purified IE63. The CTL response to IE63 was equivalent to CTL recognition of IE62, the major tegument component of VZV whose immunogenicity has been previously described. IgG Abs against IE63 were detected in serum from healthy immune adults. These results indicate that IE63 is an important target of immunity to VZV. T cell recognition of IE63 is likely to be involved in controlling VZV reactivation from latency. [less ▲]

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See detailThe VZV IE63, expressed during latency, is an efficient target for the immune system
Sadzot-Delvaux, Catherine ULg; Debrus, Serge; Kinchington, P. et al

Conference (1997)

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See detailThe VZV IE63, expressed during latency, is an efficient target for the immune system
Sadzot-Delvaux, Catherine ULg; Debrus, Serge; Kinchington, P. et al

Conference (1997)

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See detailLessons to be learned from varicella-zoster virus
Rentier, Bernard ULg; Piette, Jacques ULg; Baudoux, Laurence et al

in Veterinary Microbiology (1996), 53(1-2), 55-66

Varicella-zoster virus (VZV) is an alphaherpesvirus responsible for two human diseases: chicken pox and shingles. The virus has a respiratory port of entry. After two successive viremias, it reaches the ... [more ▼]

Varicella-zoster virus (VZV) is an alphaherpesvirus responsible for two human diseases: chicken pox and shingles. The virus has a respiratory port of entry. After two successive viremias, it reaches the skin where it causes typical lesions. There, it penetrates the peripheral nervous system and it remains latent in dorsal root ganglia. It is still debatable whether VZV persists in neurons or in satellite cells. During latency, VZV expresses a limited set of transcripts of its immediate early (IE) and early (E) genes but no protein has been detected. Mechanisms of reactivation from ganglia have not been identified. However, dysfunction of the cellular immune system appears to be involved in this process. The cell-associated nature of VZV has made it difficult to identify a temporal order of gene expression, but there appears to be a cascade mechanism as for HSV-1. The lack of high titre cell-free virions or recombination mutants has hindered so far the understanding of VZV gene functions. Five genes, ORFs 4, 10, 61, 62, and 63 that encode regulatory proteins could be involved in VZV latency. ORF4p activates gene promoters with basal activities. ORF10p seems to activate the ORF 62 promoter. ORF61p has trans-activating and trans-repressing activities. The major IE protein ORF62p, a virion component, has DNA-binding and regulatory functions, transactivates many VZV promoters and even regulates its own expression. ORF63p is a nuclear IE protein of yet unclear regulatory functions, abundantly expressed very early in infection. We have established an animal model of VZV latency in the rat nervous system, enabling us to study the expression of viral mRNA and protein expression during latency, and yielding results similar to those found in humans. This model is beginning to shed light on the molecular events in VZV persistent infection and on the regulatory mechanisms that maintain the virus in a latent stage in nerve cells. [less ▲]

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See detailIntracellular distribution of the ORF4 gene product of varicella-zoster virus is influenced by the IE62 protein
Defechereux, Patricia; Debrus, Serge; Baudoux, Laurence et al

in Journal of General Virology (1996), 77(Part 7), 1505-1513

Varicella-zoster virus (VZV) open reading frame 4-encoded protein (IE4) possesses transactivating properties for VZV genes as well as for genes of heterologous viruses, The major regulatory immediate ... [more ▼]

Varicella-zoster virus (VZV) open reading frame 4-encoded protein (IE4) possesses transactivating properties for VZV genes as well as for genes of heterologous viruses, The major regulatory immediate-early protein of VZV (IE62) is a transactivator of VZV gene expression, In transfection assays, IE4 has been shown to enhance activation induced by IE62, To investigate the functional interactions underlying this observation, indirect immunofluorescence studies were undertaken to determine whether IE62 could influence IE4 intracellular localization in transfected cells, In single transfections, IE4 was predominantly found in cytoplasm, In cotransfection with IE62, the IE4 localization pattern was altered, with nuclear staining predominating over cytoplasmic staining, This effect was specific to the IE62 protein since the gene products of ORF63 and ORF61, which are also regulatory proteins, did not influence IE4 distribution, The use of IE62 mutants indicated that IE62 influence is independent of its transactivation function and that the integrity of regions 3 and 4 is required, IE62 remained nuclear whether IE4 was present or not, These observations underline differences in the regulation of gene expression between VZV proteins and their herpes simplex virus type 1 homologues, In infected cells, IE4 was only sometimes found to colocalize with IE62 in nuclei, This observation suggests that when all VZV proteins are present, complex interactions probably occur which could diminish the influence of IE62. [less ▲]

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See detailDistribution of varicella-zoster virus and herpes simplex virus in disseminated fatal infections
Nikkels, Arjen ULg; Delvenne, Philippe ULg; Sadzot-Delvaux, Catherine ULg et al

in Journal of Clinical Pathology (1996), 49(3), 243-248

AIMS: To study the cutaneous and visceral distribution of herpes simplex virus (HSV) and varicella zoster virus (VZV) in fatal infections. METHODS: Standard histology, immunohistochemistry (monoclonal ... [more ▼]

AIMS: To study the cutaneous and visceral distribution of herpes simplex virus (HSV) and varicella zoster virus (VZV) in fatal infections. METHODS: Standard histology, immunohistochemistry (monoclonal antibodies VL8 and VL2 and polyclonal antibody IE63 directed against VZV; monoclonal antibodies IBD4 and HH2 and polyclonal antibodies directed against HSVI and HSVII) and in situ hybridisation (anti-HSV and anti-VZV probes) were applied to formalin fixed, paraffin wax sections. RESULTS: On histological examination, Herpesviridae infection was evident in various organs including the lungs, liver and skin. In addition, immunohistochemistry and in situ hybridisation revealed the presence of HSV and VZV antigens and nucleic acids in several cell types and tissues showing no cytopathological alterations suggestive of Herpesviridae infection. The organs with histological evidence of infection also contained VZV or HSV antigens and their genes. CONCLUSIONS: These findings suggest that organ failure in disseminated VZV and HSV infections is primarily caused by HSV or VZV induced cell damage and lysis. They also indicate that immunohistochemistry and in situ hybridisation can provide an accurate, type-specific diagnosis on formalin fixed, paraffin wax embedded tissue even when classic histological and cytological characteristics are lacking. [less ▲]

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See detailExpression of protein encoded by varicella-zoster virus open reading frame 63 in latently infected human ganglionic neurons
Mahalingam, Ravy; Wellish, Mary; Cohrs, Randall et al

in Proceedings of the National Academy of Sciences of the United States of America (1996), 93(5), 2122-2124

The ganglionic cell type in which varicellazoster virus (VZV) is latent in humans was analyzed by using antibodies raised against in vitro-expressed VZV open reading frame 63 protein, VZV open reading ... [more ▼]

The ganglionic cell type in which varicellazoster virus (VZV) is latent in humans was analyzed by using antibodies raised against in vitro-expressed VZV open reading frame 63 protein, VZV open reading frame 63 protein was detected exclusively in the cytoplasm of neurons of latently infected human trigeminal and thoracic ganglia. This is, to our knowledge, the first identification of a herpesvirus protein expressed during latency in the human nervous system. [less ▲]

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See detailVaricella-zoster virus gene 63 encodes an immediate-early protein that is abundantly expressed during latency
Debrus, Serge; Sadzot-Delvaux, Catherine ULg; Nikkels, Arjen ULg et al

in Journal of Virology (1995), 69(5), 3240-3245

Varicella-zoster virus (VZV) gene 63 encodes a protein with a predicted molecular mass of 30.5 kDa which has amino acid similarities with the immediate-early (IE) protein 22 (ICP-22) of herpes simplex ... [more ▼]

Varicella-zoster virus (VZV) gene 63 encodes a protein with a predicted molecular mass of 30.5 kDa which has amino acid similarities with the immediate-early (IE) protein 22 (ICP-22) of herpes simplex virus type 1. In order to study the expression of this protein during lytic and latent infection, gene 63 was cloned in frame and downstream from the glutathione-S-transferase gene, expressed as a fusion protein, and purified. In VZV-infected Vero cells, antibodies directed against this protein detect two polypeptides of 45 and 38 kDa which are localized both in the cytoplasm and in the nucleus. Using a sequential combination of transcription and protein synthesis inhibitors (actinomycin D and cycloheximide, respectively), we demonstrated the immediate-early nature of this protein, which can thus be named IE63. Using a rat model of VZV latency, we showed that IE63 is heavily expressed, essentially in neurons, during latency. IE63 can also be detected in the skin of patients showing early herpes zoster symptoms. [less ▲]

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See detailVaricella-zoster virus latency in the adult rat is a useful model for human latent infection
Sadzot-Delvaux, Catherine ULg; Debrus, Serge; Nikkels, Arjen ULg et al

in Neurology (1995), 45(12, suppl. 8), 18-20

A model of latent infection by varicella-zoster virus (VZV) was obtained in the adult rat. Inoculation of VZV-infected cells in the skin led to infection of the peripheral nervous system. Latency was ... [more ▼]

A model of latent infection by varicella-zoster virus (VZV) was obtained in the adult rat. Inoculation of VZV-infected cells in the skin led to infection of the peripheral nervous system. Latency was characterized by a long-lasting presence of the viral genome, of selected viral gene transcripts, and of at least one viral protein in the dorsal root ganglia. Reactivation has not been obtained in vivo, but has occurred ex vivo after repeated stresses. Many similarities with VZV latency in humans were found, making this model useful for vaccine and antiviral studies. [less ▲]

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See detailVaricella-zoster virus gene regulation
Piette, Jacques ULg; Defechereux, Patricia; Baudoux, Laurence et al

in Neurology (1995), 45(12, suppl. 8), 23-27

The varicella-zoster virus genome contains 71 open reading frames (ORFs), five of which (ORF62, ORF4, ORF63, ORF61, and ORF10) encode regulatory proteins. ORF62 codes for the major immediate early protein ... [more ▼]

The varicella-zoster virus genome contains 71 open reading frames (ORFs), five of which (ORF62, ORF4, ORF63, ORF61, and ORF10) encode regulatory proteins. ORF62 codes for the major immediate early protein of the virus exhibiting DNA-binding and regulatory functions. This protein, localized in the cell nucleus, is a functional homologue to ICP4 of herpes simplex virus type 1 (HSV-1). It trans-activates several varicella-zoster virus promoters of the various gene classes and autoregulates its own expression. ORF4 protein activates gene promoters provided they have basal activities, but it is not a functional homologue of HSV-1 ICP27. Gene regulation activity appears to be linked to its cysteine-rich C-terminal region. ORF63 codes for an immediate early protein mainly located in the cell nucleus. The regulatory functions it performs are still unclear. ORF61 protein is the functional homologue of HSV-1 ICPO. Its N-terminal region exhibits a RING domain responsible for trans-activating and trans-repressing activities. ORF10 protein exhibits similarities with HSV-1 VP16 and activates the ORF62 promoter. [less ▲]

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See detailDetection by PCR of varicella zoster virus DNA during primary infection in mice
Plumier, Jean-Christophe ULg; Sadzot-Delvaux, Catherine ULg; Debrus, Serge et al

in Archives Internationales de Physiologie et de Biochimie (1992), 100

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