In Vitro and In Vivo Transactivation of HIV-1 by Human Herpesvirus 6

ABSTRACT The immediate-early 2 (IE2) protein of human herpesvirus 6 is a potent transactivator of cellular and viral promoters. To better understand the biology of IE2, we generated a LexA-IE2 fusion protein and screened, using the yeast two-hybrid system, a Jurkat T-cell cDNA library for proteins that could interact with IE2. The most frequently isolated IE2-interacting protein was the human ubiquitin-conjugating enzyme 9 (Ubc9), a protein involved in the small ubiquitin-like modifier (SUMO) conjugation pathway. Using deletion mutants of IE2, we mapped the IE2-Ubc9-interacting region to residues 989 to 1037 of IE2. The interaction was found to be of functional significance to IE2, as Ubc9 overexpression significantly repressed promoter activation by IE2. The C93S Ubc9 mutant exhibited a similar effect on IE2, indicating that the E2 SUMO-conjugating function of Ubc9 is not required for its repressive action on IE2. No consensus sumoylation sites or evidence of IE2 conjugation to SUMO could be demonstrated under in vivo or in vitro conditions. Moreover, expression levels and nuclear localization of IE2 were not altered by Ubc9 overexpression, suggesting that Ubc9's repressive function likely occurs at the transcriptional complex level. Overall, our results indicate that Ubc9 influences IE2's function and provide new information on the complex interactions that occur between herpesviruses and the sumoylation pathway.

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Impact of Human Cytomegalovirus and Human Herpesvirus 6 Infection on the Expression of Factors Associated with Cell Fibrosis and Apoptosis: Clues for Implication in Systemic Sclerosis Development

International Journal of Molecular Sciences ◽

10.3390/ijms21176397 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6397

Author(s):

Maria-Cristina Arcangeletti ◽

Maria D’Accolti ◽

Clara Maccari ◽

Irene Soffritti ◽

Flora De Conto ◽

...

Keyword(s):

Systemic Sclerosis ◽

Human Cytomegalovirus ◽

Human Herpesvirus ◽

Dermal Fibroblasts ◽

Target Cells ◽

Human Herpesvirus 6 ◽

Factors Associated ◽

Herpesvirus 6

Systemic sclerosis (SSc) is a severe autoimmune disorder characterized by vasculopathy and multi-organ fibrosis; its etiology and pathogenesis are still largely unknown. Herpesvirus infections, particularly by human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6), have been suggested among triggers of the disease based on virological and immunological observations. However, the direct impact of HCMV and/or HHV-6 infection on cell fibrosis and apoptosis at the cell microenvironment level has not yet been clarified. Thus, this study aimed to investigate the effects of HCMV and HHV-6 infection on the induction of pro-fibrosis or pro-apoptosis conditions in primary human dermal fibroblasts, one of the relevant SSc target cells. The analysis, performed by microarray in in vitro HCMV- or HHV-6-infected vs. uninfected cells, using specific panels for the detection of the main cellular factors associated with fibrosis or apoptosis, showed that both viruses significantly modified the expression of at least 30 pro-fibrotic and 20 pro-apoptotic factors. Notably, several recognized pro-fibrotic factors were highly induced, and most of them were reported to be involved in vivo in the multifactorial and multistep pathogenic process of SSc, thus suggesting a potential role of both HCMV and HHV-6.

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Update on Human Herpesvirus 6 Biology, Clinical Features, and Therapy

Clinical Microbiology Reviews ◽

10.1128/cmr.18.1.217-245.2005 ◽

2005 ◽

Vol 18 (1) ◽

pp. 217-245 ◽

Cited By ~ 334

Author(s):

Leen De Bolle ◽

Lieve Naesens ◽

Erik De Clercq

Keyword(s):

Gene Expression Regulation ◽

Human Herpesvirus ◽

Central Nervous System Disease ◽

Resistance Mechanisms ◽

Host Immune System ◽

Human Herpesvirus 6 ◽

System Disease ◽

Herpesvirus 6

SUMMARY Human herpesvirus 6 (HHV-6) is a betaherpesvirus that is closely related to human cytomegalovirus. It was discovered in 1986, and HHV-6 literature has expanded considerably in the past 10 years. We here present an up-to-date and complete overview of the recent developments concerning HHV-6 biological features, clinical associations, and therapeutic approaches. HHV-6 gene expression regulation and gene products have been systematically characterized, and the multiple interactions between HHV-6 and the host immune system have been explored. Moreover, the discovery of the cellular receptor for HHV-6, CD46, has shed a new light on HHV-6 cell tropism. Furthermore, the in vitro interactions between HHV-6 and other viruses, particularly human immunodeficiency virus, and their relevance for the in vivo situation are discussed, as well as the transactivating capacities of several HHV-6 proteins. The insight into the clinical spectrum of HHV-6 is still evolving and, apart from being recognized as a major pathogen in transplant recipients (as exemplified by the rising number of prospective clinical studies), its role in central nervous system disease has become increasingly apparent. Finally, we present an overview of therapeutic options for HHV-6 therapy (including modes of action and resistance mechanisms).

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Recognition of a Novel Stage of Betaherpesvirus Latency in Human Herpesvirus 6

Journal of Virology ◽

10.1128/jvi.77.3.2258-2264.2003 ◽

2003 ◽

Vol 77 (3) ◽

pp. 2258-2264 ◽

Cited By ~ 18

Author(s):

Kazuhiro Kondo ◽

Junji Sashihara ◽

Kazuya Shimada ◽

Masaya Takemoto ◽

Kiyoko Amo ◽

...

Keyword(s):

Human Herpesvirus ◽

Intermediate Stage ◽

Viral Reactivation ◽

Immediate Early ◽

Human Herpesvirus 6 ◽

Early Protein ◽

Stable Intermediate ◽

Herpesvirus 6

ABSTRACT Latency-associated transcripts of human herpesvirus 6 (H6LTs) (K. Kondo et al. J. Virol. 76:4145-4151, 2002) were maximally expressed at a fairly stable intermediate stage between latency and reactivation both in vivo and in vitro. H6LTs functioned as sources of immediate-early protein 1 at this stage, which up-regulated the viral reactivation.

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Coinfection of SCID-hu Thy/Liv Mice with Human Herpesvirus 6 and Human Immunodeficiency Virus Type 1

Journal of Virology ◽

10.1128/jvi.74.18.8726-8731.2000 ◽

2000 ◽

Vol 74 (18) ◽

pp. 8726-8731 ◽

Cited By ~ 12

Author(s):

Alberto Gobbi ◽

Cheryl A. Stoddart ◽

Giuseppe Locatelli ◽

Fabio Santoro ◽

Christopher Bare ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Human Herpesvirus ◽

Human Herpesvirus 6 ◽

Immunodeficiency Virus ◽

Herpesvirus 6 ◽

Hiv 1

ABSTRACT Human herpesvirus 6 (HHV-6) has been proposed as a potential cofactor in the progression of human immunodeficiency virus type 1 (HIV-1) disease. We used the SCID-hu Thy/Liv mouse model to evaluate the in vivo interactions between HHV-6 and HIV-1. Our results demonstrate that HHV-6 and HIV-1 can simultaneously replicate in the human thymus in vivo. In this model, however, the presence of one virus appears not to modify the replication or cytopathicity of the other.

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Reciprocal in vitro interactions between human herpesvirus-6 and HIV-1 Tat

AIDS ◽

10.1097/00002030-199109000-00005 ◽

1991 ◽

Vol 5 (9) ◽

pp. 1095-1098 ◽

Cited By ~ 16

Author(s):

Dario Di Luca ◽

Paola Secchiero ◽

Pasqualina Bovenzi ◽

Antonella Rotola ◽

Antonella Caputo ◽

...

Keyword(s):

Human Herpesvirus ◽

Human Herpesvirus 6 ◽

Herpesvirus 6 ◽

Hiv 1 ◽

In Vitro Interactions

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Variant-Specific Tropism of Human Herpesvirus 6 in Human Astrocytes

Journal of Virology ◽

10.1128/jvi.79.15.9439-9448.2005 ◽

2005 ◽

Vol 79 (15) ◽

pp. 9439-9448 ◽

Cited By ~ 73

Author(s):

Donatella Donati ◽

Elena Martinelli ◽

Riccardo Cassiani-Ingoni ◽

Jenny Ahlqvist ◽

Jean Hou ◽

...

Keyword(s):

Glial Cells ◽

Morphological Changes ◽

Human Herpesvirus ◽

Productive Infection ◽

Human Herpesvirus 6 ◽

Viral Dna ◽

Viral Particles ◽

Herpesvirus 6

ABSTRACT Though first described as a lymphotropic virus, human herpesvirus 6 (HHV-6) is highly neuropathogenic. Two viral variants are known: HHV-6A and HHV-6B. Both variants can infect glial cells and have been differentially associated with central nervous system diseases, suggesting an HHV-6 variant-specific tropism for glial cell subtypes. We have performed infections with both viral variants in human progenitor-derived astrocytes (HPDA) and monitored infected cell cultures for cytopathic effect (CPE), intra- and extracellular viral DNA load, the presence of viral particles by electronic microscopy, mRNA transcription, and viral protein expression. HHV-6A established a productive infection with CPE, visible intracellular virions, and high virus DNA loads. HHV-6B-infected HPDA showed no morphological changes, intracellular viral particles, and decreasing intra- and extracellular viral DNA over time. After long-term passage, HHV-6B-infected HPDA had stable but low levels of intracellular viral DNA load with no detectable viral mRNA. Our results demonstrate that HHV-6A and HHV-6B have differential tropisms and patterns of infection for HPDA in vitro, where HHV-6A results in a productive lytic infection. In contrast, HHV-6B was associated with a nonproductive infection. These findings suggest that HHV-6 variants might be responsible for specific infection patterns in glial cells in vivo. Astrocytes may be an important reservoir for this virus in which differential tropism of HHV-6A and HHV-6B may be associated with different disease outcomes.

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Human Cytomegalovirus and Human Herpesvirus 6 Genes That Transform and Transactivate

Clinical Microbiology Reviews ◽

10.1128/cmr.12.3.367 ◽

1999 ◽

Vol 12 (3) ◽

pp. 367-382 ◽

Cited By ~ 54

Author(s):

Jay Doniger ◽

Sumitra Muralidhar ◽

Leonard J. Rosenthal

Keyword(s):

T Cells ◽

Tumor Suppressor ◽

Human Cytomegalovirus ◽

Human Herpesvirus ◽

Human Herpesvirus 6 ◽

Early Protein ◽

Herpesvirus 6 ◽

Transforming Proteins ◽

Hiv 1

SUMMARY This review is an update on the transforming genes of human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6). Both viruses have been implicated in the etiology of several human cancers. In particular, HCMV has been associated with cervical carcinoma and adenocarcinomas of the prostate and colon. In vitro transformation studies have established three HCMV morphologic transforming regions (mtr), i.e., mtrI, mtrII, and mtrIII. Of these, only mtrII (UL111A) is retained and expressed in both transformed and tumor-derived cells. The transforming and tumorigenic activities of the mtrII oncogene were localized to an open reading frame (ORF) encoding a 79-amino-acid (aa) protein. Furthermore, mtrII protein bound to the tumor suppressor protein p53 and inhibited its ability to transactivate a p53-responsive promoter. In additional studies, the HCMV immediate-early protein IE86 (IE2; UL122) was found to interact with cell cycle-regulatory proteins such as p53 and Rb. However, IE86 exhibited transforming activity in vitro only in cooperation with adenovirus E1A. HHV-6 is a T-cell-tropic virus associated with AIDS-related and other lymphoid malignancies. In vitro studies identified three transforming fragments, i.e., SalI-L, ZVB70, and ZVH14. Of these, only SalI-L (DR7) was retained in transformed and tumor-derived cells. The transforming and tumorigenic activities of SalI-L have been localized to a 357-aa ORF-1 protein. The ORF-1 protein was expressed in transformed cells and, like HCMV mtrII, bound to p53 and inhibited its ability to transactivate a p53-responsive promoter. HHV-6 has also been proposed to be a cofactor in AIDS because both HHV-6 and human immunodeficiency virus type 1 (HIV-1) have been demonstrated to coinfect human CD4+ T cells, causing accelerated cytopathic effects. Interestingly, like the transforming proteins of DNA tumor viruses such as simian virus 40 and adenovirus, ORF-1 was also a transactivator and specifically up-regulated the HIV-1 long terminal repeat when cotransfected into CD4+ T cells. Finally, based on the interactions of HCMV and HHV-6 transforming proteins with tumor suppressor proteins, a scheme is proposed for their role in oncogenesis.

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