The Combination of gQ1 and gQ2 in Human Herpesvirus 6A and 6B Regulates the Viral Tetramer Function for Their Receptor Recognition

Wakata, Aika; Tjan, Lidya Handayani; Nishimura, Mitsuhiro; Kawabata, Akiko; Poetranto, Anna Lystia; Yamamoto, Chisato; Arii, Jun; Mori, Yasuko

doi:10.1128/jvi.01638-20

Cited by 3 publications

(5 citation statements)

References 46 publications

(90 reference statements)

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“…At 24 h posttransfection, firefly and Renilla luciferase activities were independently assayed using the dual-luciferase reporter assay system (Promega). The luciferase activity (Fluc/Rluc) was calculated as follows: (firefly luciferase activity)/(Renilla luciferase activity) (59,63,64). To analyze the effect of inhibitors, transfected cells were untreated or treated with 10 ng of TNF-a or 10 mM colforsin as an inducer of NF-k B and CRE, respectively, at 24 h after transfection.…”

Section: Methodsmentioning

confidence: 99%

Human Herpesvirus 6A Tegument Protein U14 Induces NF-κB Signaling by Interacting with p65

Aktar

Arii

Tjan

et al. 2021

J Virol

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Viral infection induces host cells to mount a variety of immune responses, which may either limit viral propagation or create conditions conducive to virus replication in some instances. In this regard, activation of the NF-κB transcription factor is known to modulate virus replication. Human herpesvirus 6A (HHV-6A), which belongs to the Betaherpesvirinae subfamily, is frequently found in patients with neuro-inflammatory diseases, although its role in disease pathogenesis has not been elucidated. In this study, we found that the HHV-6A-encoded U14 protein activates NF-κB signaling following interaction with the NF-κB complex protein, p65. Through induction of nuclear translocation of p65, U14 increases the expression of IL-6, IL-8 and MCP-1 transcripts. We also demonstrated that activation of NF-κB signaling is important for HHV-6A replication, as inhibition of this pathway reduced virus protein accumulation and viral genome copy number. Taken together, our results suggest that HHV-6A infection activates the NF-κB pathway and promotes viral gene expression via late gene products including U14. IMPORTANCE Human herpesvirus 6A (HHV-6A) is frequently found in patients with neuro-inflammation, although its role in the pathogenesis of this disease has not been elucidated. Most viral infections activate the NF-κB pathway, which causes the transactivation of various genes, including those encoding pro-inflammatory cytokines. Our results indicate that HHV-6A U14 activates the NF-κB pathway, leading to upregulation of pro-inflammatory cytokines. We also found that activation of the NF-κB transcription factor is important for efficient viral replication. This study provides new insight into HHV-6A U14 function in host cell signaling, and identifies potential cellular targets involved in HHV-6A pathogenesis and replication.

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Section: Methodsmentioning

confidence: 99%

Human Herpesvirus 6A Tegument Protein U14 Induces NF-κB Signaling by Interacting with p65

Aktar

Arii

Tjan

et al. 2021

J Virol

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“…Upon testing this hypothesis using both immunofluorescence ( Figure 10 ) and RT-qPCR ( Figure 11 ), results showed that GAD67-positive cells are not only expressing CD134 and CD46, but CD134 expression was higher under all conditions (i.e., uninfected, HHV-6A infected, HHV-6B infected). Although the relative binding affinity of HHV-6A versus HHV-6B on each of these cell surface receptors is somewhat unclear ( 36 ; 37 ), it is known that HHV-6B can use CD46 but preferentially binds to CD134. Thus, it is reasonable to suggest that HHV-6B has an advantage over HHV-6A in terms of receptor availability, attachment, and entry into susceptible hosts.…”

Section: Discussionmentioning

confidence: 99%

Differential Impacts of HHV-6A versus HHV-6B Infection in Differentiated Human Neural Stem Cells

Bahramian

Furr

et al. 2022

Front. Immunol.

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Within the family Herpesviridae, sub-family β-herpesvirinae, and genus Roseolovirus, there are only three human herpesviruses that have been described: HHV-6A, HHV-6B, and HHV-7. Initially, HHV-6A and HHV-6B were considered as two variants of the same virus (i.e., HHV6). Despite high overall genetic sequence identity (~90%), HHV-6A and HHV-6B are now recognized as two distinct viruses. Sequence divergence (e.g., >30%) in key coding regions and significant differences in physiological and biochemical profiles (e.g., use of different receptors for viral entry) underscore the conclusion that HHV-6A and HHV-6B are distinct viruses of the β-herpesvirinae. Despite these viruses being implicated as causative agents in several nervous system disorders (e.g., multiple sclerosis, epilepsy, and chronic fatigue syndrome), the mechanisms of action and relative contributions of each virus to neurological dysfunction are unclear. Unresolved questions regarding differences in cell tropism, receptor use and binding affinity (i.e., CD46 versus CD134), host neuro-immunological responses, and relative virulence between HHV-6A versus HHV-6B prevent a complete characterization. Although it has been shown that both HHV-6A and HHV-6B can infect glia (and, recently, cerebellar Purkinje cells), cell tropism of HHV-6A versus HHV-6B for different nerve cell types remains vague. In this study, we show that both viruses can infect different nerve cell types (i.e., glia versus neurons) and different neurotransmitter phenotypes derived from differentiated human neural stem cells. As demonstrated by immunofluorescence, HHV-6A and HHV-6B productively infect VGluT1-containing cells (i.e., glutamatergic neurons) and dopamine-containing cells (i.e., dopaminergic neurons). However, neither virus appears to infect GAD67-containing cells (i.e., GABAergic neurons). As determined by qPCR, expression of immunological factors (e.g., cytokines) in cells infected with HHV-6A versus HHV6-B also differs. These data along with morphometric and image analyses of infected differentiated neural stem cell cultures indicate that while HHV-6B may have greater opportunity for transmission, HHV-6A induces more severe cytopathic effects (e.g., syncytia) at the same post-infection end points. Cumulatively, results suggest that HHV-6A is more virulent than HHV-6B in susceptible cells, while neither virus productively infects GABAergic cells. Consistency between these in vitro data and in vivo experiments would provide new insights into potential mechanisms for HHV6-induced epileptogenesis.

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“…Differences in biological characteristics, pathogenicity and genetic sequences of HHV‐6 led to identifying two variants called HHV‐6A and HHV‐6B. The similarity of these Variants' sequences is 90% 6,7 . HHV‐6A, HHV‐6B, and HHV‐7 create the Roseolovirus genus 7 .…”

Section: Introductionmentioning

confidence: 99%

“…The similarity of these Variants' sequences is 90% 6,7 . HHV‐6A, HHV‐6B, and HHV‐7 create the Roseolovirus genus 7 . HHV‐6 infection is widespread in the human population, and roseola usually occurs in the first year of infancy.…”

Section: Introductionmentioning

confidence: 99%

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Frequency evaluation and molecular characterization of HHV‐6 and HHV‐7 among children under 5 years with fever and skin rash

Keshavarz

Ghasemi

Arjeini

et al. 2023

Journal of Medical Virology

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Skin rash is one of the most common complications during childhood. Viral agents play an essential role in the development of such symptoms. Present study aims to determine the prevalence and genetic variability of Human Herpesvirus 6 and 7 (HHV‐6 and HHV‐7) infections and their subtypes in children under 5 years of age with skin rash and negative for rubella and measles. We used serum and throat swap samples from 196 children with skin rash and fever. ELISA and IFA tests were performed to detect antibodies against HHV6/7. Sequencing was performed using Sanger sequencing, and BioEdit and MEGA10 software were used for sequence analysis. According to the results, 66% and 40% of cases were positive for HHV‐6 IgM and HHV‐7 IgM, respectively. According to the molecular analysis, HHV‐6 Nested‐PCR was positive in 18% of cases, however, HHV‐7 Nested‐PCR was positive in 7.7% of cases. On the other hand, HHV‐6 IgG and HHV‐7 IgG were positive in 91% and 55% of study cases, respectively. For HHV‐6, we found some genetic variabilities resulting in antigenic changes compared to reference strains. HHV‐7 isolates showed no genetic differentiation and had a stable gene sequence. Based on the results, the detection of some cases of HHV6/7 primary infection and the presence of specific symptoms of roseola in the study population needs continuous evaluation of HHV6/7 frequency and distribution, also genetic variabilities of HHV6. This can pave the way for investigating HHV6 immune evasion and vaccine research and studying the relationship between viral genetic variations and other factors like disease severity. Furthermore, it is necessary to determine the relation between HHV6 genetic changes and latent infection to be considered in possible future vaccines and antiviral drug development.

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The Combination of gQ1 and gQ2 in Human Herpesvirus 6A and 6B Regulates the Viral Tetramer Function for Their Receptor Recognition

Cited by 3 publications

References 46 publications

Human Herpesvirus 6A Tegument Protein U14 Induces NF-κB Signaling by Interacting with p65

Human Herpesvirus 6A Tegument Protein U14 Induces NF-κB Signaling by Interacting with p65

Differential Impacts of HHV-6A versus HHV-6B Infection in Differentiated Human Neural Stem Cells

Frequency evaluation and molecular characterization of HHV‐6 and HHV‐7 among children under 5 years with fever and skin rash

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