Genomic Analysis of the Human B-Lymphotropic Virus (HBLV)

Josephs, S.F.; Salahuddin, S. Z.; Ablashi, D. V.; Schächter, François; Wong‐Staal, Flossie; Gallo, Rosella

doi:10.1126/science.3020691

Cited by 222 publications

(73 citation statements)

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“…Moreover, genes that were independent of de novo protein synthesis clustered in an area of the viral genome that has the lowest identity to the HHV-6A variant. The organization of IE genes in an area of the genome that differs from that of HHV-6A underscores the distinct differences between HHV-6B and HHV-6A and may provide a basis for further molecular and immunological analyses to elucidate their different biological behaviors.In the mid-and late 1980s human herpesvirus 6A (HHV-6A) and HHV-6B were discovered and subsequently named as variants of 20,32,34). Although they share approximately 90% nucleotide sequence identity (13, 18), the accumulating biological, genetic, and epidemiological data suggest that these viruses have independent biological functions (13,18,34,37,38).…”

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confidence: 99%

Viral Gene Expression Patterns in Human Herpesvirus 6B-Infected T Cells

Øster

Höllsberg

2002

J Virol

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Herpesvirus gene expression is divided into immediate-early (IE) or ␣ genes, early (E) or ␤ genes, and late (L) or ␥ genes on the basis of temporal expression and dependency on other gene products. By using real-time PCR, we have investigated the expression of 35 human herpesvirus 6B (HHV-6B) genes in T cells infected by strain PL-1. Kinetic analysis and dependency on de novo protein synthesis and viral DNA polymerase activity suggest that the HHV-6B genes segregate into six separate kinetic groups. The genes expressed early (groups I and II) and late (groups V and VI) corresponded well with IE and L genes, whereas the intermediate groups III and IV contained E and L genes. Although HHV-6B has characteristics similar to those of other roseoloviruses in its overall gene regulation, we detected three B-variant-specific IE genes. Moreover, genes that were independent of de novo protein synthesis clustered in an area of the viral genome that has the lowest identity to the HHV-6A variant. The organization of IE genes in an area of the genome that differs from that of HHV-6A underscores the distinct differences between HHV-6B and HHV-6A and may provide a basis for further molecular and immunological analyses to elucidate their different biological behaviors.In the mid-and late 1980s human herpesvirus 6A (HHV-6A) and HHV-6B were discovered and subsequently named as variants of 20,32,34). Although they share approximately 90% nucleotide sequence identity (13, 18), the accumulating biological, genetic, and epidemiological data suggest that these viruses have independent biological functions (13,18,34,37,38). Whereas little is known about the disease potential of HHV-6A, HHV-6B is the causative agent of the childhood disease exanthem subitum, characterized by a few days of high fever followed by a rash appearing with fever subsidence (34, 39). Thus, the frequency of HHV-6B seropositive individuals reaches almost 100% in early childhood (7, 10), but late primary infection may provoke a mononucleosislike disease similar to human cytomegalovirus (HCMV) mononucleosis. In addition, HHV-6B is thought to be involved in a number of other conditions, including encephalitis and neoplasia (2, 3).HHV-6B displays primarily tropism for T cells and monocytes (22,24). The virus enters the cells in part via binding to the ubiquitously expressed glycoprotein CD46 (33), but additional cellular proteins involved in virus entry still remain to be discovered (6, 33). As with other herpesviruses, HHV-6 establishes latency following the primary infection. In addition to its tropism for mononuclear cells, HHV-6 is highly neurotropic and may also reside in astrocytes within the central nervous system (8, 15), and it remains to be determined which cells harbor the majority of the latent virus (21, 23). Of clinical significance, HHV-6 is an important pathogen when reactivated in immunocompromised hosts, such as patients with AIDS, leukemia, lymphoma, and solid organ or bone marrow transplants (3).The entire genomes of HHV-6B strains Z29 and HST have...

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confidence: 99%

Viral Gene Expression Patterns in Human Herpesvirus 6B-Infected T Cells

Øster

Höllsberg

2002

J Virol

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“…On the basis of a diverse collection of in vivo and in vitro biological properties, HHVs are divided into three subgroups: alpha, beta, and gamma (27,28,39). Human herpesvirus 6 (HHV-6) is a ubiquitous betaherpesvirus that was first isolated in 1986 from the peripheral blood of patients with lymphoproliferative disorders (41) and AIDS (18,54). HHV-6 utilizes the cellular CD46 molecule as an entry receptor (42), predominantly infects and replicates in CD4 ϩ lymphocytes (25,51), and may establish latency in the monocyte/macrophage lineage (22).…”

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confidence: 99%

Human Herpesvirus 6 Open Reading Frame U14 Protein and Cellular p53 Interact with Each Other and Are Contained in the Virion

Takemoto

Koike

Mori

et al. 2005

J Virol

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A mass spectroscopic analysis of proteins from human herpesvirus 6 (HHV-6)-infected cells showed that the HHV-6 U14 protein coimmunoprecipitated with the tumor suppressor p53. The binding of U14 to p53 was verified by coimmunoprecipitation experiments in both Molt-3 cells infected with HHV-6 and 293 cells cotransfected with U14 and p53 expression vectors. Indirect immunofluorescence assays (IFAs) showed that by 18 h postinfection (hpi) U14 localized to the dot-like structures observed in both the nucleus and cytoplasm where p53 was partly accumulated. Despite Northern blotting evidence that U14 follows late kinetics, the U14 protein was detected immediately after infection (at 3 hpi) by IFA. In addition, by Western blotting, U14 was detected at 0 hpi or in the presence of cycloheximide which completely abolished the expression of IE1 protein.In addition to U14, p53 was detected at 0 hpi although it was not detected in mock-infected cells. Furthermore, both U14 and p53 were clearly detected in the viral particles by Western blotting and immunoelectron microscopy, supporting the idea that U14 and p53 are incorporated into virions. Our study provides the first evidence of the incorporation of cellular p53 into viral particles and suggests that p53 may play an important role in viral infection.

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“…Properties of genome and genetics. The virus genome is a linear, doublestranded DNA molecule with a size of 160-170 kbp containing a central segment of a largely unique sequence (U) of approximately 140 kbp having a sequence of approximately 10 kbp duplicated in the same orientation at both left and right genomic termini (TR) (38,69). The density of the genomic DNA is approximately 1.702 g/cm3 and a mean G C content is 43% (53).…”

Section: Latent Infection and The Reactivation Of Hhv-6 (mentioning

confidence: 99%

Human Herpesvirus 6

Yamanishi

1992

Microbiology and Immunology

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551 552K. YAMANISHI balloon-like cells could be observed. When the cells were fixed and stained with the sera of acute and convalescent phase of ES, positive staining was observed only with the convalescent sera. Next, the cultured cells were observed by electron microscopy (EM) as reported elsewhere (74). The typical herpesvirus particles were found in the nucleus and cytoplasm of the cultured cells. Thus, the diameter of virion was 90-110 nm in the nucleus and 150-170 nm in the cytoplasm (91, 95), suggesting that this virus resembles a herpesvirus. Next, sera, which were specific for 5 human pathogenic herpesviruses described above, were tested for the reactivity to this viral antigen in the cultured cells, and no positive staining was observed. These results suggested that a new herpesvirus was isolated from ES patients. Then this viral antigen and HHV-6 antigen (55) were reacted with paired sera from ES patients. No antibody to both antigens was detected in the sera during the acute phase and the antibody titers to both antigens increased during the convalescent phase. This result indicated that the virus isolated from ES patients was HHV-6. Thereafter this result was confirmed by other groups, and the virus isolation rate from ES patients was shown to be high at the febrile phase of ES (6, 13). Furthermore, it was reported that HHV-6 infection without clinical symptoms of rash or fever, or even without any clinical symptoms could be seen in some individuals as the primary infection of 81,83).3. Other diseases associated with HHV-6 infection. Although the symptoms of ES are relatively mild, liver dysfunction and neurological symptoms such as convulsion are seen during ES (62). Recently it has been reported that HHV-6 caused the liver dysfunction in the patients who were in the primary infection of HHV-6 (9, 82, 88), and that unfortunately one patient died from fulminant hepatitis (9).A case that was diagnosed as encephalitis during HHV-6 infection was also reported (36). In order to detect HHV-6 in the central nervous system, we tried to detect HHV-6 DNA in the cerebrospinal fluid (CSF) from ES patients (93). CSF was obtained from patients showing the neurological symptoms, such as convulsion, vomiting, irritability and bulging of anterior fontanel, during febrile phase of ES. Since patients had high fever (more than 39 C) and the appearance of rash after subsidence of the fever, they were clinically diagnosed as ES. When cell counts in CSF were performed at the time of sample collection, they ranged in normal in each sample. CSF samples as controls were collected from patients who were admitted in the hospital and suspected as having neurological symptoms or lasting high fever by unknown causes. Sixteen specimens including 6 control samples of CSF were collected from the patients, and DNA was extracted and amplified by PCR using HHV-6 specific primers. The band specific for HHV-6 DNA could be detected by ethidium bromide staining in 5 of the 10 ES patients, CSF (50%), and this was confirmed by Southern blot...

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Genomic Analysis of the Human B-Lymphotropic Virus (HBLV)

Cited by 222 publications

References 6 publications

Viral Gene Expression Patterns in Human Herpesvirus 6B-Infected T Cells

Viral Gene Expression Patterns in Human Herpesvirus 6B-Infected T Cells

Human Herpesvirus 6 Open Reading Frame U14 Protein and Cellular p53 Interact with Each Other and Are Contained in the Virion

Human Herpesvirus 6

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