scholarly journals Human Cytomegalovirus and Human Herpesvirus 6 Genes That Transform and Transactivate

1999 ◽  
Vol 12 (3) ◽  
pp. 367-382 ◽  
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.

scholarly journals 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

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.

scholarly journals Phenotypic and Functional Differences between Human Herpesvirus 6- and Human Cytomegalovirus-Specific T Cells

2019 ◽  
Vol 93 (13) ◽  
Author(s):  
Solène Fastenackels ◽  
Charles Bayard ◽  
Martin Larsen ◽  
Philippe Magnier ◽  
Pascale Bonnafous ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Cytomegalovirus ◽  
Ex Vivo ◽  
Human Herpesvirus ◽  
T Cell Responses ◽  
Effector Memory ◽  
Human Herpesvirus 6 ◽  
Cell Responses ◽  
Herpesvirus 6

ABSTRACTHuman herpesvirus 6 (HHV-6) infects >90% of the population and establishes a latent infection with asymptomatic episodes of reactivation. However, HHV-6 reactivation is associated with morbidity and sometimes mortality in immunocompromised patients. To date, control of the virus in healthy virus carriers and the failure to control it in patients with disease remain poorly understood. In particular, knowledge of HHV-6-specific T-cell responses is limited. Here, we characterized HHV-6A- and HHV-6B-specific CD4+and CD8+T-cell responses from peripheral blood mononuclear cells (PBMCs) of healthy donors. We studied the phenotype of effector HHV-6-specific T cellsex vivo, as well as of induced specific suppressive regulatory CD4+T cellsin vitropoststimulation, in comparison to human cytomegalovirus (HCMV) responses. Compared to that for HCMV, we show thatex vivoT-cell reactivity in peripheral blood is detectable but at very low frequency, both for HHV-6A and -6B viruses. Interestingly, the phenotype of the specific T cells also differs between the viruses. HHV-6A- and HHV-6B-specific CD4+T lymphocytes are less differentiated than HCMV-specific T cells. Furthermore, we show a higher frequency of HHV-6-specific suppressive regulatory T cells (eTregs) than HCMV-specific eTregs in coinfected individuals. Despite the strong similarity of HHV-6 and HCMV from a virologic point of view, we observed immunological differences, particularly in relation to the frequency and phenotype of effector/memory and regulatory virus-specific T cells. This suggests that different immune factors are solicited in the control of HHV-6 infection than in that of HCMV infection.IMPORTANCET cells are central to an effective defense against persistent viral infections that can be related to human cytomegalovirus (HCMV) or human herpesvirus 6 (HHV-6). However, knowledge of HHV-6-specific T-cell responses is limited. In order to deepen our knowledge of T-cell responses to HHV-6, we characterized HHV-6A- and HHV-6B-specific CD4+and CD8+T-cell responses directlyex vivofrom healthy coinfected blood donors. Despite the strong similarity of HHV-6 and HCMV from a virologic point of view, we observed immunological differences, particularly in relation to the frequency and phenotype of effector/memory and regulatory virus-specific T cells. This suggests that different immune factors are solicited in the control of HHV-6 infection than in that of HCMV infection. Our findings may encourage immunomonitoring of patients with viral replication episodes to follow the emergence of effector versus regulatory T cells.

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

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

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

2003 ◽  
Vol 77 (3) ◽  
pp. 2258-2264 ◽  
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.

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

AIDS ◽  
1991 ◽  
Vol 5 (9) ◽  
pp. 1095-1098 ◽  
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

scholarly journals Modulation of microRNome by Human Cytomegalovirus and Human Herpesvirus 6 Infection in Human Dermal Fibroblasts: Possible Significance in the Induction of Fibrosis in Systemic Sclerosis

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1060
Author(s):  
Irene Soffritti ◽  
Maria D’Accolti ◽  
Gloria Ravegnini ◽  
Maria-Cristina Arcangeletti ◽  
Clara Maccari ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Human Cytomegalovirus ◽  
Mirna Expression ◽  
Human Herpesvirus ◽  
Dermal Fibroblasts ◽  
Target Cells ◽  
Human Dermal Fibroblasts ◽  
Human Herpesvirus 6 ◽  
Herpesvirus 6

Human cytomegalovirus (HCMV) and Human herpesvirus 6 (HHV-6) have been reportedly suggested as triggers of the onset and/or progression of systemic sclerosis (SSc), a severe autoimmune disorder characterized by multi-organ fibrosis. The etiology and pathogenesis of SSc are still largely unknown but virological and immunological observations support a role for these beta-herpesviruses, and we recently observed a direct impact of HCMV and HHV-6 infection on the expression of cell factors associated with fibrosis at the cell level. Since miRNA expression has been found profoundly deregulated at the tissue level, here we aimed to investigate the impact on cell microRNome (miRNome) of HCMV and HHV-6 infection in in vitro infected primary human dermal fibroblasts, which represent one of the main SSc target cells. The analysis, performed by Taqman arrays detecting and quantifying 754 microRNAs (miRNAs), showed that both herpesviruses significantly modulated miRNA expression in infected cells, with evident early and late effects and deep modulation (>10 fold) of >40 miRNAs at each time post infection, including those previously recognized for their key function in fibrosis. The correlation between these in vitro results with in vivo observations is strongly suggestive of a role of HCMV and/or HHV-6 in the multistep pathogenesis of fibrosis in SSc and in the induction of fibrosis-signaling pathways finally leading to tissue fibrosis. The identification of specific miRNAs may open the way to their use as biomarkers for SSc diagnosis, assessment of disease progression and possible antifibrotic therapies.

scholarly journals Role of dendritic cells infected with human herpesvirus 6 in virus transmission to CD4+ T cells

Virology ◽  
2009 ◽  
Vol 385 (2) ◽  
pp. 294-302 ◽  
Author(s):  
Masaya Takemoto ◽  
Takayoshi Imasawa ◽  
Koichi Yamanishi ◽  
Yasuko Mori
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd4 T Cells ◽  
Virus Transmission ◽  
Human Herpesvirus ◽  
Human Herpesvirus 6 ◽  
Herpesvirus 6

scholarly journals Immunosuppressive effect of human herpesvirus 6 on T-cell functions: suppression of interleukin-2 synthesis and cell proliferation [published erratum appears in Blood 1995 Jul 1;86(1):418]

Blood ◽  
1995 ◽  
Vol 85 (5) ◽  
pp. 1263-1271 ◽  
Author(s):  
L Flamand ◽  
J Gosselin ◽  
I Stefanescu ◽  
D Ablashi ◽  
J Menezes
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocyte ◽  
Peripheral Blood ◽  
Cellular Proliferation ◽  
Interleukin 2 ◽  
Human Herpesvirus ◽  
Human Herpesvirus 6 ◽  
Infected Cells ◽  
Herpesvirus 6

Human herpesvirus-6 (HHV-6), the etiologic agent of roseola, is ubiquitous, establishes latency in the host, and can infect a variety of immunocompetent cells, with CD4+ T lymphocytes being the targets in which it replicates most efficiently. The present study was undertaken to learn more about specific immunobiologic effects of HHV-6 infection on T-lymphocyte functions. Our data demonstrate that infection of peripheral blood mononuclear cells (PBMC) by HHV-6 results in suppression of T-lymphocyte functions, as evidenced by reduced interleukin-2 (IL-2) synthesis and cellular proliferation. In fact, HHV- 6-infected PBMC secreted 50% less IL-2 than mock-infected cells after mitogenic stimulation with OKT3 antibody or phytohemmaglutinin (PHA). The inhibition of IL-2 by HHV-6 was also observed in enriched T-cell cultures, suggesting a direct effect of this virus on this cell type. Messenger RNA (mRNA) analysis by reverse-transcriptase polymerase chain reaction (PCR) indicated that HHV-6 diminishes IL-2 mRNA levels in mitogen-stimulated peripheral blood T cells. These results were also confirmed by Northern blot using the leukemic T-cell line Jurkat. This inhibitory effect of HHV-6 did not require infectious virus, as the use of UV-irradiated HHV-6 produced similar results. Moreover, HHV-6- infected PBMC showed up to an 85% reduction in their mitogen-driven proliferative response, as compared with sham-infected cells. Proliferation of both CD4+ and CD8+ T cells was affected by HHV-6. Taken together, our data show that infection of T cells by HHV-6 results in immune suppression characterized by a downregulation of IL-2 mRNA and protein synthesis accompanied by diminished cellular proliferation.

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

1988 ◽  
Vol 167 (5) ◽  
pp. 1659-1670 ◽  
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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