Review part 2: Human herpesvirus‐6 in central nervous system diseases

Yao, Karen; Crawford, John R.; Komaroff, Anthony L.; Ablashi, Dharam V.; Jacobson, Steven

doi:10.1002/jmv.21861

Cited by 102 publications

(92 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A growing number of studies have linked HHV-6 infection to different neurological diseases, such as multiple sclerosis, chronic fatigue syndrome, and epilepsy (65,66). However, host factors that contribute to protective and pathological immune responses to HHV-6 remain undefined.…”

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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…Furthermore, reactivation of HHV-6, suggested by an increase in viral load and antibody titers, has been associated with CNS pathologies such as encephalitis, meningitis, and multiple sclerosis (MS) (64,84). HHV-6 reactivation also has been associated with chronic fatigue syndrome (CFS) (41), febrile seizures (83), myocarditis (3,14), pityriasis rosea (23), and drug-induced hypersensitivity syndrome (DIHS) (8).…”

mentioning

confidence: 99%

Human CD4⁺T Cell Response to Human Herpesvirus 6

Nastke

Becerra

Yin

et al. 2012

J Virol

View full text Add to dashboard Cite

Following primary infection, human herpesvirus 6 (HHV-6) establishes a persistent infection for life. HHV-6 reactivation has been associated with transplant rejection, delayed engraftment, encephalitis, muscular dystrophy, and drug-induced hypersensitivity syndrome. The poor understanding of the targets and outcome of the cellular immune response to HHV-6 makes it difficult to outline the role of HHV-6 in human disease. To fill in this gap, we characterized CD4 T cell responses to HHV-6 using peripheral blood mononuclear cell (PBMC) and T cell lines generated from healthy donors. CD4؉ T cells responding to HHV-6 in peripheral blood were observed at frequencies below 0.1% of total T cells but could be expanded easily in vitro. Analysis of cytokines in supernatants of PBMC and T cell cultures challenged with HHV-6 preparations indicated that gamma interferon (IFN-␥) and interleukin-10 (IL-10) were appropriate markers of the HHV-6 cellular response. Eleven CD4 ؉ T cell epitopes, all but one derived from abundant virion components, were identified. The response was highly cross-reactive between HHV-6A and HHV-6B variants. Seven of the CD4 ؉ T cell epitopes do not share significant homologies with other known human pathogens, including the closely related human viruses human herpesvirus 7 (HHV-7) and human cytomegalovirus (HCMV). Major histocompatibility complex (MHC) tetramers generated with these epitopes were able to detect HHV-6-specific T cell populations. These findings provide a window into the immune response to HHV-6 and provide a basis for tracking HHV-6 cellular immune responses.

show abstract

“…[11][12][13][14][15] HHV6 enters the central nervous system through the olfactory pathway and replicates in neural cells, but the primary targets of HHV6 replication are CD4+ and T-cells, B-cells, monocytes, macrophages, and epithelial cells. [4][5][6][7] This case report is not a proof of cause, but the repeated consistent falls in HHV6 serum antibody titer and the apparent clinical response to cidofovir are striking ( Cidofovir is an acyclic phosphonate nucleotide analog of deoxycytidine monophosphate.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 Other potentially nephrotoxic agents, ie, aminoglycosides or nonsteroidal anti-inflammatory agents, should be avoided during treatment with cidofovir. 8,[11][12][13][14] Cidofovir and probenecid share small sulfur moieties and may cause sulfur toxicity. Preliminary testing with initial small doses of cidofovir are indicated if sulfonamide sensitivity is suspected.…”

Section: Discussionmentioning

confidence: 99%

Beneficial response of cervical dystonia spasmodic torticollis to cidofovir, an acyclic phosphonate analog (s-1-3-hydroxy-2- phosphonylmethoxypropyl) of cytosine

Lerner¹,

Beqaj²

2014

VAAT

View full text Add to dashboard Cite

Abstract:We report the case of a 23-year-old healthy man who had sudden onset of cervical dystonia spasmodic torticollis in October 2012. He was treated with intravenous cidofovir, which was started on February 20, 2013, followed by oral valganciclovir and famciclovir. Pulling of the neck and tilt of the head far to the left is no longer present (as at April 22, 2014). Human herpesvirus 6 total antibody titers fell from 11.27 (negative ,1) on January 15, 2013 to 1.89 on August 5, 2013. To our knowledge, this is the first case of improvement in cervical dystonia spasmodic torticollis with treatment.

show abstract

Review part 2: Human herpesvirus‐6 in central nervous system diseases

Abstract: J. Med. Virol. 82:1669–1678, 2010. © 2010 Wiley‐Liss, Inc.

Cited by 102 publications

References 96 publications

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

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

Human CD4⁺T Cell Response to Human Herpesvirus 6

Beneficial response of cervical dystonia spasmodic torticollis to cidofovir, an acyclic phosphonate analog (s-1-3-hydroxy-2- phosphonylmethoxypropyl) of cytosine

Contact Info

Product

Resources

About

Review part 2: Human herpesvirus‐6 in central nervous system diseases

Abstract: J. Med. Virol. 82:1669–1678, 2010. © 2010 Wiley‐Liss, Inc.

Cited by 102 publications

References 96 publications

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

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

Human CD4+T Cell Response to Human Herpesvirus 6

Beneficial response of cervical dystonia spasmodic torticollis to cidofovir, an acyclic phosphonate analog (s-1-3-hydroxy-2- phosphonylmethoxypropyl) of cytosine

Contact Info

Product

Resources

About

Human CD4⁺T Cell Response to Human Herpesvirus 6