Downregulation of the T-Cell Receptor Complex and Impairment of T-Cell Activation by Human Herpesvirus 6 U24 Protein

Sullivan, Brian M.; Coscoy, Laurent

doi:10.1128/jvi.01571-07

Cited by 61 publications

(65 citation statements)

References 48 publications

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“…In HHV-6B, U54 inhibits expression of interleukin 2 (IL-2), an important growth factor for T-cell homeostasis (27), by preventing the dephosphorylation of NFAT (nuclear factor of activated T cells), thereby blocking its downstream transcriptional activation of the IL-2 gene (28). HHV-6A U24 is a protein that downregulates CD3, which signals downstream of the T-cell receptor (29). The MRV genome does not appear to have a U24 homolog at the corresponding position.…”

Section: Resultsmentioning

confidence: 99%

A Murine Herpesvirus Closely Related to Ubiquitous Human Herpesviruses Causes T-Cell Depletion

Patel

Zhao

Penna

et al. 2017

J Virol

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The human roseoloviruses human herpesvirus 6A (HHV-6A), HHV-6B, and HHV-7 comprise the Roseolovirus genus of the human Betaherpesvirinae subfamily. Infections with these viruses have been implicated in many diseases; however, it has been challenging to establish infections with roseoloviruses as direct drivers of pathology, because they are nearly ubiquitous and display species-specific tropism. Furthermore, controlled study of infection has been hampered by the lack of experimental models, and until now, a mouse roseolovirus has not been identified. Herein we describe a virus that causes severe thymic necrosis in neonatal mice, characterized by a loss of CD4 ϩ T cells. These phenotypes resemble those caused by the previously described mouse thymic virus (MTV), a putative herpesvirus that has not been molecularly characterized. By next-generation sequencing of infected tissue homogenates, we assembled a contiguous 174-kb genome sequence containing 128 unique predicted open reading frames (ORFs), many of which were most closely related to herpesvirus genes. Moreover, the structure of the virus genome and phylogenetic analysis of multiple genes strongly suggested that this virus is a betaherpesvirus more closely related to the roseoloviruses, HHV-6A, HHV-6B, and HHV-7, than to another murine betaherpesvirus, mouse cytomegalovirus (MCMV). As such, we have named this virus murine roseolovirus (MRV) because these data strongly suggest that MRV is a mouse homolog of HHV-6A, HHV-6B, and HHV-7.IMPORTANCE Herein we describe the complete genome sequence of a novel murine herpesvirus. By sequence and phylogenetic analyses, we show that it is a betaherpesvirus most closely related to the roseoloviruses, human herpesviruses 6A, 6B, and 7. These data combined with physiological similarities with human roseoloviruses collectively suggest that this virus is a murine roseolovirus (MRV), the first definitively described rodent roseolovirus, to our knowledge. Many biological and clinical ramifications of roseolovirus infection in humans have been hypothesized, but studies showing definitive causative relationships between infection and disease susceptibility are lacking. Here we show that MRV infects the thymus and causes T-cell depletion, suggesting that other roseoloviruses may have similar properties.KEYWORDS herpesviruses, roseolovirus T he study of herpesviruses has been fruitful, not only revealing mechanisms that drive disease but also providing insight into diverse processes, including oncogenesis and immune regulation (1). The Herpesviridae family includes several highly prevalent human pathogens (1-3). While they are related, these viruses have diverse genomes,

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Section: Resultsmentioning

confidence: 99%

A Murine Herpesvirus Closely Related to Ubiquitous Human Herpesviruses Causes T-Cell Depletion

Patel

Zhao

Penna

et al. 2017

J Virol

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“…In marked contrast to herpesviruses such as CMV and EBV, the interaction of HHV-6 and the immune system was interpreted predominantly in terms of the immunosuppressive effects of the virus [16]. Because HHV-6 may inhibit T cells [17,18,36] and APCs [19,37] by a variety of mechanisms, some of them operative only in infected cells but some also in bystander cells, HHV-6 has been described as an immunosuppressive virus [16]. This has left open the question how healthy carriers control HHV-6 infection, and how virus-specific T cells may contribute to control, although such knowledge is essential for an understanding of HHV-6 disease and the development of new (immuno) therapies.…”

Section: Discussionmentioning

confidence: 99%

Specific CD8⁺T cells recognize human herpesvirus 6B

et al. 2012

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The importance of human herpesvirus 6 (HHV-6) species as human pathogens is increasingly appreciated. However, we do not understand how infection is controlled in healthy virus carriers, and why control fails in patients with disease. Other persistent viruses are under continuous surveillance by antigen-specific T cells, and specific T-cell repertoires have been well characterized for some of them. In contrast, knowledge on HHV-6-specific T-cell responses is limited, and missing for CD8 + T cells. Here we identify CD8 + T-cell responses to HHV-6B, the most widespread HHV-6 species, in healthy virus carriers. HHV-6B-specific CD8 + T-cell lines and clones recognized HLA-A2-restricted peptides from the viral structural proteins U54 and U11, and displayed various antigenspecific antiviral effector functions. These CD8 + T cells specifically recognized HHV-6B-infected primary CD4 + T cells in an HLA-restricted manner, produced antiviral cytokines, and killed infected cells, whereas HHV-6A-infected cells were not recognized. Thus, HHV-6B-specific CD8 + T cells are likely to contribute to control of infection, overcoming the immunomodulatory effects exerted by the virus. Potentially, HHV-6-associated disease could be addressed by active or passive immunotherapy that reconstitutes virusspecific CD8 + T-cell responses. Keywords: CD8+ T cells r human herpesvirus 6B r infectious diseases r virology IntroductionHuman herpesvirus 6 (HHV-6) species are widespread pathogens, and more than 90% of humans are seropositive. The two species HHV-6A and HHV-6B have close sequence homology but differ in their epidemiology and pathogenicity [1,2]. Primary infection with HHV-6B, the more widespread species, usually takes place in early childhood and is often associated with a self-limiting illness known as three-day fever or exanthema subitum [3,4]. After primary infection, HHV-6 remains in a latent state in its immunocompetent host [5], and occasional reactivations are normally asymptomatic. However, HHV-6 (in most cases HHV-6B) can reactivate in immunosuppressed individuals. HHV-6B reactivation is observed in 40-50% of patients receiving stem cell transCorrespondence: Dr. Andreas Moosmann e-mail: andreas.moosmann@helmholtz-muenchen.de plantation, and viral reactivation is associated with delirium and cognitive decline, severe encephalitis, graft-versus-host disease, transplant failure, and overall mortality [6][7][8][9]. Apart from the immunosuppressed host, HHV-6 has been involved in a variety of diseases involving the CNS, such as febrile seizures, encephalitis, epilepsy, and multiple sclerosis [2,10]. Healthy humans frequently carry a number of other persistent viruses that may reactivate under immunosuppression, including the herpesvirus family members Epstein-Barr virus (EBV) and cytomegalovirus (CMV) [11]. It is assumed that these viruses are under continuous control by antigen-specific T cells, and viral reactivation results from a deficiency in virus-specific T cells caused by therapy-related immunosuppression [11]. In accorda...

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“…Similar to HIV-infected cells, HHV-6-infected CD4 ϩ T cells express low levels of TCR-CD3 molecules (34). This phenotype results from a block in CD3 transcription (33) as well as from an inhibition of the constitutive recycling of the CD3 and TCR molecules back to the plasma membrane (57). Inhibition of TCR/CD3 recycling is mediated by U24, an HHV-6 gene product.…”

mentioning

confidence: 99%

“…Transfection of U24 in T-cell lines mediates a rapid relocalization of the CD3 and TCR molecules from the plasma membrane to early endosomes. As a consequence, U24-expressing cells are impaired in their ability to become activated (57).…”

mentioning

confidence: 99%

The U24 Protein from Human Herpesvirus 6 and 7 Affects Endocytic Recycling

Sullivan

Coscoy

2010

J Virol

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Modulation of T-cell receptor expression and signaling is essential to the survival of many viruses. The U24 protein expressed by human herpesvirus 6A, a ubiquitous human pathogen, has been previously shown to downregulate the T-cell receptor. Here, we show that U24 also mediates cell surface downregulation of a canonical early endosomal recycling receptor, the transferrin receptor, indicating that this viral protein acts by blocking early endosomal recycling. We present evidence that U24 is a C-tail-anchored protein that is dependent for its function on TRC40/Asna-1, a component of a posttranslational membrane insertion pathway. Finally, we find that U24 proteins from other roseoloviruses have a similar genetic organization and a conserved function that is dependent on a proline-rich motif. Inhibition of a basic cellular process by U24 has interesting implications not only for the pathogenicity of roseoloviruses but also for our understanding of the biology of endosomal transport.

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Downregulation of the T-Cell Receptor Complex and Impairment of T-Cell Activation by Human Herpesvirus 6 U24 Protein

Cited by 61 publications

References 48 publications

A Murine Herpesvirus Closely Related to Ubiquitous Human Herpesviruses Causes T-Cell Depletion

A Murine Herpesvirus Closely Related to Ubiquitous Human Herpesviruses Causes T-Cell Depletion

Specific CD8⁺T cells recognize human herpesvirus 6B

The U24 Protein from Human Herpesvirus 6 and 7 Affects Endocytic Recycling

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Downregulation of the T-Cell Receptor Complex and Impairment of T-Cell Activation by Human Herpesvirus 6 U24 Protein

Cited by 61 publications

References 48 publications

A Murine Herpesvirus Closely Related to Ubiquitous Human Herpesviruses Causes T-Cell Depletion

A Murine Herpesvirus Closely Related to Ubiquitous Human Herpesviruses Causes T-Cell Depletion

Specific CD8+T cells recognize human herpesvirus 6B

The U24 Protein from Human Herpesvirus 6 and 7 Affects Endocytic Recycling

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Specific CD8⁺T cells recognize human herpesvirus 6B