LAT Region Factors Mediating Differential Neuronal Tropism of HSV-1 and HSV-2 Do Not Act in Trans

Bertke, Andrea S.; Apakupakul, Kathleen; Ma, AyeAye; Imai, Yumi; Gussow, Anne M.; Wang, Kening; Cohen, Jeffrey I.; Bloom, David C.; Margolis, Todd P.

doi:10.1371/journal.pone.0053281

Cited by 13 publications

(12 citation statements)

References 20 publications

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“…Therefore, we coinfected AMTC with HSV-1/LAT2 and HSV-2-green fluorescent protein (GFP) (12) and assayed the pattern of productive infection of each virus. Only 5% of KH10ϩ neurons were productively infected with HSV-1/LAT2, similar to percentages with either HSV-2 or HSV-2-GFP alone ( 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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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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“…To determine if HSV-1 and HSV-2 could reactivate from individual autonomic neurons, mice were infected with HSV-1 or HSV-2 viruses that express a VP26-GFP fusion protein during replication. VP26, expressed by a late gene, is a small capsid protein that decorates the outer surface of the mature capsids, bound to VP5 (20)(21)(22); previous studies have demonstrated that the HSV VP26-GFP reporter viruses effectively represent productive infection (3,5). Twenty-one days postinfection, when the viruses had established latency, TG, SCG, and CG were removed from infected mice, cultured, and observed for viral reactivation, visualized by expression of GFP in individual neurons.…”

Section: Resultsmentioning

confidence: 99%

“…Sensory neurons recognized by monoclonal antibody Fe-A5 (A5ϩ) limit productive HSV-1 infection (3,4). In contrast, sensory neurons bound by the monoclonal antibody KH10 or isolectin IB4 (IB4ϩ) limit productive infection of HSV-2 (3)(4)(5). Similar percentages of these nonoverlapping populations of sen-sory neurons are found in TG (10 to 12%) and DRG (13 to 15%).…”

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“…HSV-1 and HSV-2 demonstrate neuronal specificity for A5ϩ and IB4ϩ neurons, respectively, regardless of the route of infection. One-half of the LAT-positive latent HSV-1 reservoir is found in A5ϩ neurons, and one-half of the LAT-positive latent HSV-2 reservoir is found in IB4ϩ neurons, in the TG after ocular infection or in the DRG after genital infection (5)(6)(7)(8)(9). Thus, different patterns of HSV-1 and HSV-2 recurrence cannot be adequately explained by preferential establishment of latency in different types of sensory neurons.…”

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Herpes Simplex Virus 1 Reactivates from Autonomic Ciliary Ganglia Independently from Sensory Trigeminal Ganglia To Cause Recurrent Ocular Disease

Lee

Ives

Bertke

2015

J Virol

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Herpes simplex virus 1 (HSV-1) and HSV-2 establish latency in sensory and autonomic neurons after ocular or genital infection, but their recurrence patterns differ. HSV-1 reactivates from latency to cause recurrent orofacial disease, and while HSV-1 also causes genital lesions, HSV-2 recurs more efficiently in the genital region and rarely causes ocular disease. The mechanisms regulating these anatomical preferences are unclear. To determine whether differences in latent infection and reactivation in autonomic ganglia contribute to differences in HSV-1 and HSV-2 anatomical preferences for recurrent disease, we compared HSV-1 and HSV-2 clinical disease, acute and latent viral loads, and viral gene expression in sensory trigeminal and autonomic superior cervical and ciliary ganglia in a guinea pig ocular infection model. HSV-2 produced more severe acute disease, correlating with higher viral DNA loads in sensory and autonomic ganglia, as well as higher levels of thymidine kinase expression, a marker of productive infection, in autonomic ganglia. HSV-1 reactivated in ciliary ganglia, independently from trigeminal ganglia, to cause more frequent recurrent symptoms, while HSV-2 replicated simultaneously in autonomic and sensory ganglia to cause more persistent disease. While both HSV-1 and HSV-2 expressed the latency-associated transcript (LAT) in the trigeminal and superior cervical ganglia, only HSV-1 expressed LAT in ciliary ganglia, suggesting that HSV-2 is not reactivation competent or does not fully establish latency in ciliary ganglia. Thus, differences in replication and viral gene expression in autonomic ganglia may contribute to differences in HSV-1 and HSV-2 acute and recurrent clinical disease. IMPORTANCEHerpes simplex virus 1 (HSV-1) and HSV-2 establish latent infections, from which the viruses reactivate to cause recurrent disease throughout the life of the host. However, the viruses exhibit different manifestations and frequencies of recurrent disease. HSV-1 and HSV-2 establish latency in both sensory and autonomic ganglia. Autonomic ganglia are more responsive than sensory ganglia to stimuli associated with recurrent disease in humans, such as stress and hormone fluctuations, suggesting that autonomic ganglia may play an important role in recurrent disease. We show that HSV-1 can reactivate from autonomic ganglia, independently from sensory ganglia, to cause recurrent ocular disease. We found no evidence that HSV-2 could reactivate from autonomic ganglia independently from sensory ganglia after ocular infection, but HSV-2 did replicate in both ganglia simultaneously to cause persistent disease. Thus, viral replication and reactivation in autonomic ganglia contribute to different clinical disease manifestations of HSV-1 and HSV-2 after ocular infection. Herpes simplex virus 1 (HSV-1) and HSV-2 infect and establish latency in peripheral sensory ganglia, including the trigeminal ganglia (TG) after orofacial infection and the dorsal root ganglia (DRG) after genital infection. While both viruses ca...

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“…Observations obtained with mouse neurons point to the relevance of the differential expression of neurotrophic factor receptors in different neurons and its effect on the establishment of HSV latency [22]. Indeed, the differential expression of neurotrophic factor receptor and other neuronal markers in mouse neurons seems to be linked to the preference of HSV-1 or HSV-2 to establish latency in distinct subpopulations of mouse sensory neurons [27,28]. In particular, NGF dependent neurons seem to support HSV-2 productive infection, but not latency, whereas the contrary is true for HSV-1 [27].…”

Section: Discussionmentioning

confidence: 99%

Herpes Simplex Virus and Neurotrophic Factors

VB¹

2015

JHVRV

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LAT Region Factors Mediating Differential Neuronal Tropism of HSV-1 and HSV-2 Do Not Act in Trans

Cited by 13 publications

References 20 publications

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

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

Herpes Simplex Virus 1 Reactivates from Autonomic Ciliary Ganglia Independently from Sensory Trigeminal Ganglia To Cause Recurrent Ocular Disease

Herpes Simplex Virus and Neurotrophic Factors

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