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

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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Functional Interaction between Human Herpesvirus 6 Immediate-Early 2 Protein and Ubiquitin-Conjugating Enzyme 9 in the Absence of Sumoylation

Journal of Virology ◽

10.1128/jvi.00375-06 ◽

2006 ◽

Vol 80 (20) ◽

pp. 10218-10228 ◽

Cited By ~ 21

Author(s):

Andru Tomoiu ◽

Annie Gravel ◽

Robert M. Tanguay ◽

Louis Flamand

Keyword(s):

Human Herpesvirus ◽

Immediate Early ◽

Human Herpesvirus 6 ◽

Interacting Protein ◽

Ubiquitin Conjugating Enzyme ◽

Herpesvirus 6 ◽

Transcriptional Complex ◽

Conjugating Enzyme

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

HIV-Host Interactions ◽

10.5772/19778 ◽

2011 ◽

Author(s):

Ongradi Joseph ◽

Kovesdi Valeria ◽

Nagy Karoly ◽

Matteoli Barbara ◽

Ceccherini-Nelli Luca ◽

...

Keyword(s):

Human Herpesvirus ◽

Human Herpesvirus 6 ◽

Herpesvirus 6 ◽

Hiv 1

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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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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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In vitro and in vivo analysis of human herpesvirus-6 U90 protein expression

Journal of Medical Virology ◽

10.1002/jmv.20241 ◽

2004 ◽

Vol 75 (1) ◽

pp. 86-92 ◽

Cited By ~ 5

Author(s):

N. Nishimura ◽

T. Yoshikawa ◽

T. Ozaki ◽

H. Sun ◽

F. Goshima ◽

...

Keyword(s):

Protein Expression ◽

Human Herpesvirus ◽

Human Herpesvirus 6 ◽

In Vivo Analysis ◽

Herpesvirus 6

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In vitro susceptibility of T lymphocytes from chimpanzees (Pan troglodytes) to human herpesvirus 6 (HHV-6): a potential animal model to study the interaction between HHV-6 and human immunodeficiency virus type 1 in vivo.

Journal of Virology ◽

10.1128/jvi.64.6.2751-2758.1990 ◽

1990 ◽

Vol 64 (6) ◽

pp. 2751-2758 ◽

Cited By ~ 26

Author(s):

P Lusso ◽

P D Markham ◽

S E DeRocco ◽

R C Gallo

Keyword(s):

Human Immunodeficiency Virus ◽

Animal Model ◽

Pan Troglodytes ◽

Human Herpesvirus ◽

Human Herpesvirus 6 ◽

In Vitro Susceptibility ◽

Immunodeficiency Virus

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In vitro cellular tropism of human B-lymphotropic virus (human herpesvirus-6).

Journal of Experimental Medicine ◽

10.1084/jem.167.5.1659 ◽

1988 ◽

Vol 167 (5) ◽

pp. 1659-1670 ◽

Cited By ~ 217

Author(s):

P Lusso ◽

P D Markham ◽

E Tschachler ◽

F di Marzo Veronese ◽

S Z Salahuddin ◽

...

Keyword(s):

T Cell ◽

T Lymphocytes ◽

Cell Population ◽

Mononuclear Cells ◽

Human Herpesvirus ◽

Human Herpesvirus 6 ◽

Infected Cells ◽

Cellular Tropism ◽

Herpesvirus 6

We investigated the cellular tropism of human B-lymphotropic virus (HBLV) (also designated Human Herpesvirus-6) in vitro by infecting fresh MN cells from normal human adult peripheral blood, umbilical cord blood, bone marrow, tonsil, and thymus. Cultures from all the sources examined contained infectable cells, as shown by the appearance of characteristic enlarged, round-shaped, short-lived cells expressing HBLV-specific markers. Detailed immunological analysis demonstrated that the vast majority of these cells expressed T cell-associated antigens (i.e., CD7, CD5, CD2, CD4, and to a lesser extent, CD8). The CD3 antigen and the TCR-alpha/beta heterodimer were not detectable on the surface membrane, but were identified within the cytoplasm of HBLV-infected cells, by both immunofluorescence and radioimmunoprecipitation assay. A proportion of the HBLV-infected cell population also expressed the CD15 and class II MHC DR antigens. By means of immunoselection procedures it was possible to show that a consistent proportion of HBLV-infectable cells were contained within the CD3-depleted immature T cell population, while the depletion of CD2+ cells completely abrogated the infectability of the cultures. Northern blot analysis confirmed the T cell origin of HBLV-infected cells, demonstrating the expression of full size TCR-alpha and -beta chain mRNA. In addition to fresh T cells, HBLV was able to infect normal T lymphocytes expanded in vitro with IL-2 for greater than 30 d. These results indicate that HBLV is selectively T cell tropic in the course of the in vitro infection of normal mononuclear cells and may therefore be directly involved in the pathogenesis of T cell related hematological disorders. In particular, in light of the cytopathic effect exerted in vitro on CD4+ T lymphocytes, a possible role of HBLV in immune deficiency conditions should be considered.

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