Retrograde axonal transport of VZV: kinetic studies in hESC-derived neurons

Grigoryan, Sergei; Kinchington, Paul R.; Yang, In Hong; Selariu, Anca; Zhu, Hua; Yee, Michael B.; Goldstein, Ronald S.

doi:10.1007/s13365-012-0124-z

Cited by 39 publications

(44 citation statements)

References 29 publications

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“…These results are similar to quiescent HSV-1 in neurons obtained from adult murine trigeminal ganglia wherein RNA-seq data suggest transcription from multiple regions of the virus genome in addition to LAT (Harkness et al, 2014). As the neurons can be maintained in compartmented microfluidic chambers that orientate neurite outgrowth, infection of axons with fluorescently tagged virus permits direct viewing of retrograde transport to neuronal cell bodies (Markus et al, 2011;Grigoryan et al, 2012). These nearpure (w95 % bIII-tubulin expressing) neuronal cultures provide an excellent opportunity to observe the outcome of VZV infection, such as induction of host anti-apoptotic genes (Markus et al, 2014), although latency (long-term presence of VZV DNA with limited transcription) has not yet been obtained.…”

Section: Alphaherpesvirus Gene Transcription Is Deregulated During VIsupporting

confidence: 68%

A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation

Kennedy

Rovnak

Badani

et al. 2015

Journal of General Virology

137

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Herpes simplex virus type 1 (HSV-1; human herpesvirus 1) and varicella-zoster virus (VZV; human herpesvirus 3) are human neurotropic alphaherpesviruses that cause lifelong infections in ganglia. Following primary infection and establishment of latency, HSV-1 reactivation typically results in herpes labialis (cold sores), but can occur frequently elsewhere on the body at the site of primary infection (e.g. whitlow), particularly at the genitals. Rarely, HSV-1 reactivation can cause encephalitis; however, a third of the cases of HSV-1 encephalitis are associated with HSV-1 primary infection. Primary VZV infection causes varicella (chickenpox) following which latent virus may reactivate decades later to produce herpes zoster (shingles), as well as an increasingly recognized number of subacute, acute and chronic neurological conditions. Following primary infection, both viruses establish a latent infection in neuronal cells in human peripheral ganglia. However, the detailed mechanisms of viral latency and reactivation have yet to be unravelled. In both cases latent viral DNA exists in an 'end-less' state where the ends of the virus genome are joined to form structures consistent with unit length episomes and concatemers, from which viral gene transcription is restricted. In latently infected ganglia, the most abundantly detected HSV-1 RNAs are the spliced products originating from the primary latency associated transcript (LAT). This primary LAT is an 8.3 kb unstable transcript from which two stable (1.5 and 2.0 kb) introns are spliced. Transcripts mapping to 12 VZV genes have been detected in human ganglia removed at autopsy; however, it is difficult to ascribe these as transcripts present during latent infection as early-stage virus reactivation may have transpired in the post-mortem time period in the ganglia. Nonetheless, low-level transcription of VZV ORF63 has been repeatedly detected in multiple ganglia removed as close to death as possible. There is increasing evidence that HSV-1 and VZV latency is epigenetically regulated. In vitro models that permit pathway analysis and identification of both epigenetic modulations and global transcriptional mechanisms of HSV-1 and VZV latency hold much promise for our future understanding in this complex area. This review summarizes the molecular biology of HSV-1 and VZV latency and reactivation, and also presents future directions for study. Received 5 January 2015Accepted 18 March 2015 IntroductionHerpes simplex virus type 1 (HSV-1; human herpesvirus 1) and varicella-zoster virus (VZV; human herpesvirus 3) are human neurotropic alphaherpesviruses usually acquired early in life. Primary HSV-1 infection is usually localized and may be asymptomatic, although it can produce a more widespread systemic infection in neonates and immunocompromised adults, whilst primary VZV infection is systemic and results in childhood varicella (chickenpox). During primary infection, both viruses gain access to neurons most likely through retrograde transport from the site of cutaneous lesion...

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Section: Alphaherpesvirus Gene Transcription Is Deregulated During VIsupporting

confidence: 68%

A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation

Kennedy

Rovnak

Badani

et al. 2015

Journal of General Virology

137

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“…Herpes zoster associated with varicella vaccine is most common at the site of the vaccine inoculation (43), and about 50% of zoster cases associated with vaccination are due to WT virus (50). Also, VZV has previously been shown to enter neurons in vitro from nerve endings by cell-to-cell contact with infected cells or cell-free virus followed by transaxonal transport to the soma (16,17,21).…”

Section: Discussionmentioning

confidence: 99%

“…The use of stem cell-derived neurons contrasts with the use of neurons from sensory or cranial nerve ganglia isolated from human cadavers, most of which have already been infected with VZV. Neurons from hESCs fully support lytic infection after infection with cellassociated POka VZV of either the cell body (soma) or axons through retrograde transport using compartmented microfluidic chambers (16,17). In this model, the cellular transcriptome in…”

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confidence: 99%

In vitro system using human neurons demonstrates that varicella-zoster vaccine virus is impaired for reactivation, but not latency

Sadaoka

Depledge

Rajbhandari

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

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Varicella-zoster virus (VZV) establishes latency in human sensory and cranial nerve ganglia during primary infection (varicella), and the virus can reactivate and cause zoster after primary infection. The mechanism of how the virus establishes and maintains latency and how it reactivates is poorly understood, largely due to the lack of robust models. We found that axonal infection of neurons derived from hESCs in a microfluidic device with cell-free parental Oka (POka) VZV resulted in latent infection with inability to detect several viral mRNAs by reverse transcriptase-quantitative PCR, no production of infectious virus, and maintenance of the viral DNA genome in endless configuration, consistent with an episome configuration. With deep sequencing, however, multiple viral mRNAs were detected. Treatment of the latently infected neurons with Ab to NGF resulted in production of infectious virus in about 25% of the latently infected cultures. Axonal infection of neurons with vaccine Oka (VOka) VZV resulted in a latent infection similar to infection with POka; however, in contrast to POka, VOka-infected neurons were markedly impaired for reactivation after treatment with Ab to NGF. In addition, viral transcription was markedly reduced in neurons latently infected with VOka compared with POka. Our in vitro system recapitulates both VZV latency and reactivation in vivo and may be used to study viral vaccines for their ability to establish latency and reactivate. varicella-zoster virus | varicella vaccine | reactivation | latency | herpesvirus V aricella-zoster virus (VZV) is a member of Alphaherpesvirinae, characterized by neurotropism and lifelong latent infection in human dorsal root, cranial nerve, and enteric ganglia (1). During primary infection (varicella), VZV gains access to sensory neurons by two potential routes: retrograde axonal transport from cutaneous lesions or infection of neurons by virus-infected T cells circulating through the body (2). The virus then establishes latency in neurons, and months to years later, when VZV-specific T cells decline, the virus can reactivate to cause herpes zoster.VZV is the only human herpesvirus for which a licensed vaccine is approved, and the live-attenuated vaccine Oka (VOka) virus is effective in preventing both varicella and zoster. VOka was derived from WT parental Oka (POka) by propagation in human embryonic lung cells, guinea pig embryo fibroblasts, and human fibroblasts (3, 4). VOka is a genetic mixture of at least eight genotypes (5), and, initially, the genomes of POka and VOka were found to differ by 42 nucleotides and 20 amino acids (6). A recent study using deep sequencing identified 165 additional nucleotide changes in VOka, although most changes were presence in <10% of viral genomes (7). Attenuation of VOka is postulated to be due to mutations in multiple regions of the genome (8, 9).Despite numerous studies, the mechanisms for establishment and maintenance of VZV latency and subsequent reactivation remain poorly understood, primarily due to the lack of ...

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“…ORF7 is non-essential for VZV growth in vitro but has dual roles as virulence determinants in human skin and DRG tissue ex vivo/in vivo (Zhang et al, 2010;Selariu et al, 2012). Recently, several further studies have demonstrated that deletion of ORF7 does not prevent viral entry, viral replication and viral protein expression as well as retrograde transport of virus particles from axon terminals to somata but substantially affects secondary envelopment and cell-to-cell spread of VZV in differentiated neuronal cells in vitro (Grigoryan et al, 2012;Jiang et al, 2017). On the other hand, ORF53 is essential for VZV replication (Zhang et al, 2010), however, its characteristics have remain unstudied to date.…”

Section: Discussionmentioning

confidence: 99%

Varicella-zoster virus ORF7 interacts with ORF53 and plays a role in its trans-Golgi network localization

Wang

Pan

et al. 2017

Virol. Sin.

Self Cite

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Varicella-zoster virus (VZV) is a neurotropic alphaherpesvirus that causes chickenpox andshingles. ORF7 is an important virulence determinant of VZV in both human skin and nerve tissues, however, its specific function and involved molecular mechanism in VZV pathogenesis remain largely elusive. Previous yeast two-hybrid studies on intraviral protein-protein interaction network in herpesviruses have revealed that VZV ORF7 may interact with ORF53, which is a virtually unstudied but essential viral protein. The aim of this study is to identify and characterize VZV ORF53, and to investigate its relationship with ORF7. For this purpose, we prepared monoclonal antibodies against ORF53 and, for the first time, characterized it as a ~40 kDa viral protein predominantly localizing to the trans-Golgi network of the infected host cell. Next, we further confirmed the interaction between ORF7 and ORF53 by co-immunoprecipitation and co-localization studies in both plasmid-transfected and VZV-infected cells. Moreover, interestingly, we found that ORF53 lost its trans-Golgi network localization and became dispersed in the cytoplasm of host cells infected with an ORF7-deleted recombinant VZV, and thus ORF7 seems to play a role in normal subcellular localization of ORF53. Collectively, these results suggested that ORF7 and ORF53 may function as a complex during infection, which may be implicated in VZV pathogenesis. KEYWORDSvaricella-zoster virus (VZV); ORF7; ORF53; protein-protein interaction; trans-Golgi network

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Retrograde axonal transport of VZV: kinetic studies in hESC-derived neurons

Cited by 39 publications

References 29 publications

A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation

A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation

In vitro system using human neurons demonstrates that varicella-zoster vaccine virus is impaired for reactivation, but not latency

Varicella-zoster virus ORF7 interacts with ORF53 and plays a role in its trans-Golgi network localization

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