Investigation of the Mechanism by Which Herpes Simplex Virus Type 1 LAT Sequences Modulate Preferential Establishment of Latent Infection in Mouse Trigeminal Ganglia

Imai, Yumi; Apakupakul, Kathleen; Krause, Philip R.; Halford, William P.; Margolis, Todd P.

doi:10.1128/jvi.00043-09

Cited by 18 publications

(38 citation statements)

References 67 publications

(76 reference statements)

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“…In previous studies, we used combined fluorescent in situ hybridization (FISH) for the LAT in conjunction with immunofluorescence (IF) for neuronal markers to demonstrate that HSV-1 preferentially establishes latent infection of murine sensory ganglia in A5-positive neurons while HSV-2 preferentially establishes latent infection in KH10-positive neurons after ocular or footpad infection of mice (21,28). One mechanism that could account for these findings is differential permissiveness of different types of sensory neurons for productive infection with HSV-1 and HSV-2.…”

Section: Resultsmentioning

confidence: 99%

“…We have demonstrated previously that HSV-1 and HSV-2 preferentially establish latency and express the latency-associated transcript (LAT) in different populations of neurons, identified by the A5 and KH10 markers, within sensory ganglia (21,28,52). Although all neuronal populations are thought to be capable of supporting productive HSV infection, some neuronal populations of the trigeminal ganglion (TG) appear to be more permissive for productive infection than others, and the permissiveness of neuronal subtypes differs for HSV-1 and HSV-2.…”

Section: Herpes Simplex Viruses 1 and 2 (Hsv-1 And Hsv-2) Establish Lmentioning

confidence: 99%

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A5-Positive Primary Sensory Neurons Are Nonpermissive for Productive Infection with Herpes Simplex Virus 1 In Vitro

Bertke

Swanson

Chen

et al. 2011

J Virol

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120

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Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) establish latency and express the latency-associated transcript (LAT) preferentially in different murine sensory neuron populations, with most HSV-1 LAT expression in A5؉ neurons and most HSV-2 LAT expression in KH10 ؉ neurons. To study the mechanisms regulating the establishment of HSV latency in specific subtypes of neurons, cultured dissociated adult murine trigeminal ganglion (TG) neurons were assessed for relative permissiveness for productive infection. In contrast to that for neonatal TG, the relative distribution of A5 ؉ and KH10 ؉ neurons in cultured adult TG was similar to that seen in vivo. Productive infection with HSV was restricted, and only 45% of cultured neurons could be productively infected with either HSV-1 or HSV-2. A5؉ neurons supported productive infection with HSV-2 but were selectively nonpermissive for productive infection with HSV-1, a phenomenon that was not due to restricted viral entry or DNA uncoating, since HSV-1 expressing ␤-galactosidase under the control of the neurofilament promoter was detected in ϳ90% of cultured neurons, with no preference for any neuronal subtype. Infection with HSV-1 reporter viruses expressing enhanced green fluorescent protein (EGFP) from immediate early (IE), early, and late gene promoters indicated that the block to productive infection occurred before IE gene expression. Trichostatin A treatment of quiescently infected neurons induced productive infection preferentially from non-A5 ؉ neurons, demonstrating that the nonpermissive neuronal subtype is also nonpermissive for reactivation. Thus, HSV-1 is capable of entering the majority of sensory neurons in vitro; productive infection occurs within a subset of these neurons; and this differential distribution of productive infection is determined at or before the expression of the viral IE genes.Herpes simplex virus 1 and 2 (HSV-1 and HSV-2) replication at the periphery is accompanied by infection of neuronal axons and subsequent retrograde axonal transport to cell bodies of primary sensory neurons, where infection may follow either a productive or a latent pathway. For some neurons, lytic gene expression and progeny virus production are thought to result in cell death, while in other neurons, the productive cycle fails and the virus establishes a latent infection. The factors that determine whether HSV progresses through a productive cycle or establishes latency are not clear. It is suspected that different neuronal subtypes and/or the presence or absence of certain host factors may be critical in determining the outcome of infection.Primary sensory neurons are a diverse population of cells that are classified according to cellular morphology, physiological response properties, and patterns of gene expression. We have demonstrated previously that HSV-1 and HSV-2 preferentially establish latency and express the latency-associated transcript (LAT) in different populations of neurons, identified by the A5 and KH10 markers, within sensory ganglia (21,28,52). ...

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Section: Resultsmentioning

confidence: 99%

Section: Herpes Simplex Viruses 1 and 2 (Hsv-1 And Hsv-2) Establish Lmentioning

confidence: 99%

A5-Positive Primary Sensory Neurons Are Nonpermissive for Productive Infection with Herpes Simplex Virus 1 In Vitro

Bertke

Swanson

Chen

et al. 2011

J Virol

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120

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“…In round-trip infection, virus replicates in the neuron, travels anterograde to the skin and produces fresh lesions. Virus within the new skin lesions travels back to the ganglia to infect more neurons (Simmons & Nash, 1985;Imai et al, 2009). The outcome of virus infection, in part, may depend upon the specific class of neurons infected.…”

Section: Introductionmentioning

confidence: 99%

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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“…2C) (11), has a latent phenotype similar to that of wild-type (WT) HSV-2 in vivo (6). In AMTC, HSV-1/LAT2 productively infects A5ϩ and KH10ϩ neurons equivalently (30% and 31%, respectively), in contrast to HSV-1 and the rescuant, which infect 3% of A5ϩ neurons and 22% of KH10ϩ neurons (Fig.…”

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confidence: 99%

Different Mechanisms Regulate Productive Herpes Simplex Virus 1 (HSV-1) and HSV-2 Infections in Adult Trigeminal Neurons

Bertke

Margolis

et al. 2013

J Virol

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Herpes simplex virus 1 (HSV-1) and HSV-2 establish latency in different neuronal subtypes (A5؉ and KH10؉) in murine trigeminal ganglia, results which correlate with restricted productive infection in these neurons in vitro. HSV-2 latency-associated transcript (LAT) contains a cis-acting regulatory element near the transcription start site that promotes productive infection in A5؉ neurons and a second element in exon 1 that inhibits productive infection in KH10؉ neurons. HSV-1 contains no such regulatory sequences, demonstrating different mechanisms for regulating productive HSV infection in neurons. Herpes simplex virus 1 (HSV-1) and HSV-2 express productive cycle genes in some neurons and establish latent infection in others. We previously demonstrated that HSV-1 and HSV-2 preferentially establish latency in different neuronal subtypes in murine sensory ganglia: HSV-1 in A5ϩ neurons and HSV-2 in KH10ϩ neurons (1, 2). In dissociated adult murine trigeminal cultures (AMTC), we previously found that HSV-1 productively infected KH10ϩ but not A5ϩ neurons while HSV-2 productively infected A5ϩ but not KH10ϩ neurons (Fig. 1A) (3). Thus, the neuronal subtypes that restrict productive HSV infection in vitro are the same neurons that harbor latent infection in vivo. Both host and viral factors may play roles in regulating neuronal specificity (1, 2, 4-7). To determine if the latency-associated transcript (LAT) region regulates productive infection in A5ϩ and KH10ϩ neurons, we assayed HSV infection of AMTC using a series of LAT deletion and chimeric viruses (5).The HSV-2 LAT region contains two regulatory sequences for productive infection of neurons. HSV-2 (333) productively infects 36% of A5ϩ neurons in AMTC but only 3% of KH10ϩ neurons (Fig. 1B). In contrast, dLAT (NotI-NotI deletion of the HSV-2 LAT promoter) (Fig. 1D) (8) productively infects only 5% of A5ϩ neurons (Fig. 1B). The LAP2 virus (LAT promoter 2 deletion in HSV-2 exon 1) (Fig. 1D) (9) productively infects A5ϩ and KH10ϩ neurons equivalently (39% and 36%, respectively) (Fig. 1B). Thus, two distinct functional elements within HSV-2 LAT regulate productive infection: the NotI-NotI region promotes productive infection in A5ϩ neurons, and the LAP2 region inhibits productive infection in KH10ϩ neurons.HSV-2/LAT1 is a chimera in which 2.8 kb of the HSV-2 LAT region (promoter, exon 1, and ϳ1.5 kb of the intron, excluding ICP0 coding sequences) was replaced by the same region from HSV-1 (10). HSV-2/LAT1 preferentially establishes latency in A5ϩ neurons in vivo, suggesting that HSV-1 LAT in the context of HSV-2 changes the viral phenotype to that of HSV-1 (1). In AMTC, HSV-2/LAT1 productively infects 22% of KH10ϩ neurons but only 4% of A5ϩ neurons, in contrast to HSV-2 or the rescuant, HSV-2/LAT1-R (Fig. 1C). Thus, the pattern of productive infection with HSV-2/LAT1 resembles that of HSV-1, with productive infection in KH10ϩ neurons but restricted infection in A5ϩ neurons. Since the HSV-1 LAT region in HSV-2/LAT1 replaces sequences that were deleted in dLAT and LAP2, ...

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Investigation of the Mechanism by Which Herpes Simplex Virus Type 1 LAT Sequences Modulate Preferential Establishment of Latent Infection in Mouse Trigeminal Ganglia

Cited by 18 publications

References 67 publications

A5-Positive Primary Sensory Neurons Are Nonpermissive for Productive Infection with Herpes Simplex Virus 1 In Vitro

A5-Positive Primary Sensory Neurons Are Nonpermissive for Productive Infection with Herpes Simplex Virus 1 In Vitro

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

Different Mechanisms Regulate Productive Herpes Simplex Virus 1 (HSV-1) and HSV-2 Infections in Adult Trigeminal Neurons

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