Human Herpesvirus 6 Latent Infection in Patients With Glioma

Chi, Jing; Gu, Bin; Zhang, Chun; Peng, Guangyong; Feng, Zijian; Chen, Yun; Zhang, Guofeng; Guo, Yidi; Guo, Dandan; Qin, Jian; Wang, Jinfeng; Li, Lingyun; Wang, Fang; Liu, Genyan; Xie, Fang; Feng, Dan; Zhou, Hong; Huang, Xingxu; Lu, Shiqiang; Liu, Yingxia; Hu, Weixing; Yao, Kun

doi:10.1093/infdis/jis513

Cited by 51 publications

(53 citation statements)

References 14 publications

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“…HHV-6 infection may be associated with the nodular sclerosing (NS)-type Hodgkin lymphoma and angioimmunoblastic T cell lymphoma (AITL). In addition, recent studies from our group and others demonstrated that HHV-6 may also be associated with glioma (5)(6)(7)(8).…”

mentioning

confidence: 69%

Development of Virus-Specific CD4 ⁺ and CD8 ⁺ Regulatory T Cells Induced by Human Herpesvirus 6 Infection

Wang

Chi

Peng

et al. 2014

J Virol

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؉ effector T cell immune responses but also could impair dendritic cell (DC) maturation and functions. In addition, the suppressive effects mediated by HHV-6-specific Treg cells were mainly through a cell-to-cell contact-dependent mechanism but not through the identified cytokines. These results suggest that HHV-6 may utilize the induction of Treg cells as a strategy to escape antivirus immune responses and maintain the latency and immunosuppression in infected hosts.

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mentioning

confidence: 69%

Development of Virus-Specific CD4 ⁺ and CD8 ⁺ Regulatory T Cells Induced by Human Herpesvirus 6 Infection

Wang

Chi

Peng

et al. 2014

J Virol

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“…Therefore, we cannot exclude that some other nontested RNA transcripts, potentially different from those known to be associated with latency in human cells, are expressed during HHV-6A infection in the murine brain and participate in the persistence of HHV-6A. Viral RNA and proteins are very rarely detected in the brain of healthy people harboring HHV-6A DNA without HHV-6-related pathology (7,8,12,71). In humans, HHV-6 infection of tissue in vivo seems to be much less efficient than that in vitro.…”

Section: Discussionmentioning

confidence: 99%

Human Herpesvirus 6A Infection in CD46 Transgenic Mice: Viral Persistence in the Brain and Increased Production of Proinflammatory Chemokines via Toll-Like Receptor 9

Reynaud

Jégou

Welsch

et al. 2014

J Virol

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Human herpesvirus 6 (HHV-6) is widely spread in the human population and has been associated with several neuroinflammatory diseases, including multiple sclerosis. To develop a small-animal model of HHV-6 infection, we analyzed the susceptibility of several lines of transgenic mice expressing human CD46, identified as a receptor for HHV-6. We showed that HHV-6A (GS) infection results in the expression of viral transcripts in primary brain glial cultures from CD46-expressing mice, while HHV-6B (Z29) infection was inefficient. HHV-6A DNA persisted for up to 9 months in the brain of CD46-expressing mice but not in the nontransgenic littermates, whereas HHV-6B DNA levels decreased rapidly after infection in all mice. Persistence in the brain was observed with infectious but not heat-inactivated HHV-6A. Immunohistological studies revealed the presence of infiltrating lymphocytes in periventricular areas of the brain of HHV-6A-infected mice. Furthermore, HHV-6A stimulated the production of a panel of proinflammatory chemokines in primary brain glial cultures, including CCL2, CCL5, and CXCL10, and induced the expression of CCL5 in the brains of HHV-6A-infected mice. HHV-6A-induced production of chemokines in the primary glial cultures was dependent on the stimulation of toll-like receptor 9 (TLR9). Finally, HHV-6A induced signaling through human TLR9 as well, extending observations from the murine model to human infection. Altogether, this study presents a first murine model for HHV-6A-induced brain infection and suggests a role for TLR9 in the HHV-6A-initiated production of proinflammatory chemokines in the brain, opening novel perspectives for the study of virus-associated neuropathology. IMPORTANCEHHV-6 infection has been related to neuroinflammatory diseases; however, the lack of a suitable small-animal infection model has considerably hampered further studies of HHV-6-induced neuropathogenesis. In this study, we have characterized a new model for HHV-6 infection in mice expressing the human CD46 protein. Infection of CD46 transgenic mice with HHV-6A resulted in long-term persistence of viral DNA in the brains of infected animals and was followed by lymphocyte infiltration and upregulation of the CCL5 chemokine in the absence of clinical signs of disease. The secretion of a panel of chemokines was increased after infection in primary murine brain glial cultures, and the HHV-6-induced chemokine expression was inhibited when TLR9 signaling was blocked. These results describe the first murine model for HHV-6A-induced brain infection and suggest the importance of the TLR9 pathway in HHV-6A-initiated neuroinflammation.

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“…Marmosets inoculated with HHV-6A intravenously exhibited neurological symptoms, whereas those inoculated with HHV-6B were asymptomatic [75]. A strain of HHV-6A has also recently been isolated from the fluid specimens from a glioma cyst [30]. Moreover, HHV-6A was identified in 72 % of pediatric glial tumors [38].…”

Section: Distinct Epidemiology and Disease Associationsmentioning

confidence: 99%

Classification of HHV-6A and HHV-6B as distinct viruses

et al. 2013

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Shortly after the discovery of human herpesvirus 6 (HHV-6), two distinct variants, HHV-6A and HHV-6B, were identified. In 2012, the International Committee on Taxonomy of Viruses (ICTV) classified HHV-6A and HHV-6B as separate viruses. This review outlines several of the documented epidemiological, biological, and immunological distinctions between HHV-6A and HHV-6B, which support the ICTV classification. The utilization of virus-specific clinical and laboratory assays for distinguishing HHV-6A and HHV-6B is now required for further classification. For clarity in biological and clinical distinctions between HHV-6A and HHV-6B, scientists and physicians are herein urged, where possible, to differentiate carefully between HHV-6A and HHV-6B in all future publications.

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Human Herpesvirus 6 Latent Infection in Patients With Glioma

Cited by 51 publications

References 14 publications

Development of Virus-Specific CD4 ⁺ and CD8 ⁺ Regulatory T Cells Induced by Human Herpesvirus 6 Infection

Development of Virus-Specific CD4 ⁺ and CD8 ⁺ Regulatory T Cells Induced by Human Herpesvirus 6 Infection

Human Herpesvirus 6A Infection in CD46 Transgenic Mice: Viral Persistence in the Brain and Increased Production of Proinflammatory Chemokines via Toll-Like Receptor 9

Classification of HHV-6A and HHV-6B as distinct viruses

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Human Herpesvirus 6 Latent Infection in Patients With Glioma

Cited by 51 publications

References 14 publications

Development of Virus-Specific CD4 + and CD8 + Regulatory T Cells Induced by Human Herpesvirus 6 Infection

Development of Virus-Specific CD4 + and CD8 + Regulatory T Cells Induced by Human Herpesvirus 6 Infection

Human Herpesvirus 6A Infection in CD46 Transgenic Mice: Viral Persistence in the Brain and Increased Production of Proinflammatory Chemokines via Toll-Like Receptor 9

Classification of HHV-6A and HHV-6B as distinct viruses

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Development of Virus-Specific CD4 ⁺ and CD8 ⁺ Regulatory T Cells Induced by Human Herpesvirus 6 Infection

Development of Virus-Specific CD4 ⁺ and CD8 ⁺ Regulatory T Cells Induced by Human Herpesvirus 6 Infection