The Role of LAT in Increased CD8
            <sup>+</sup>
            T Cell Exhaustion in Trigeminal Ganglia of Mice Latently Infected with Herpes Simplex Virus 1

Allen, Sariah J.; Hamrah, Pedram; Gate, David; Mott, Kevin R.; Mantopoulos, Dimosthenis; Zheng, Lixin; Town, Terrence; Jones, Clinton; Andrian, Ulrich H. von; Freeman, Gordon J.; Sharpe, Arlene H.; BenMohamed, Lbachir; Ahmed, Rafi; Wechsler, Steven L.; Ghiasi, Homayon

doi:10.1128/jvi.02290-10

Cited by 106 publications

(219 citation statements)

References 82 publications

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“…was determined by quantitative PCR (qPCR) using primers from the gB region of the HSV-1 genome. Consistent with previous reports (12,49), there was significantly more HSV-1 DNA in TG from WT mice latently infected with LAT(ϩ) virus than in those infected with LAT(Ϫ) virus (Fig. 3A, WT) (P Ͻ 0.0001), which is characteristic of more latency with LAT(ϩ) than LAT(Ϫ) virus in WT mice.…”

Section: Hsv-1 Receptors and Latencysupporting

confidence: 92%

“…We have previously shown that LAT functions as an immune evasion gene (49,65), as an antiapoptosis gene (11), and as an inhibitor of productive infection (45). All three of these LAT functions would seemingly contribute to enhancing HSV-1 latency and the HSV-1 reactivation phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…ing the time required for production of infectious virus (9,(49)(50)(51)(52). Consistent with previous studies, the time to reactivation in WT mice was significantly shorter with LAT(ϩ) virus than with LAT(Ϫ) virus (5.6 Ϯ 0.2 days versus 6.3 Ϯ 0.2 days; P ϭ 0.02) (Fig.…”

Section: Hsv-1 Receptors and Latencymentioning

confidence: 99%

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Interactions between Herpesvirus Entry Mediator (TNFRSF14) and Latency-Associated Transcript during Herpes Simplex Virus 1 Latency

Allen

Rhode-Kurnow

Mott

et al. 2014

J Virol

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f Herpesvirus entry mediator (HVEM) is one of several cell surface proteins herpes simplex virus (HSV) uses for attachment/entry. HVEM regulates cellular immune responses and can also increase cell survival. Interestingly, latency-associated transcript (LAT), the only viral gene consistently expressed during neuronal latency, enhances latency and reactivation by promoting cell survival and by helping the virus evade the host immune response. However, the mechanisms of these LAT activities are not well understood. We show here for the first time that one mechanism by which LAT enhances latency and reactivation appears to be by upregulating HVEM expression. HSV-1 latency/reactivation was significantly reduced in Hvem ؊/؊ mice, indicating that HVEM plays a significant role in HSV-1 latency/reactivation. Furthermore, LAT upregulated HVEM expression during latency in vivo and also when expressed in vitro in the absence of other viral factors. This study suggests a mechanism whereby LAT upregulates HVEM expression potentially through binding of two LAT small noncoding RNAs to the HVEM promoter and that the increased HVEM then leads to downregulation of immune responses in the latent microenvironment and increased survival of latently infected cells. Thus, one of the mechanisms by which LAT enhances latency/reactivation appears to be through increasing expression of HVEM.

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Section: Hsv-1 Receptors and Latencysupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Interactions between Herpesvirus Entry Mediator (TNFRSF14) and Latency-Associated Transcript during Herpes Simplex Virus 1 Latency

Allen

Rhode-Kurnow

Mott

et al. 2014

J Virol

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“…+ T-cells (Theil et al, 2003a;Verjans et al, 2007) that are primed in the periphery (Held et al, 2012) and LAT functions in part to protect neurons from granzyme B-induced apoptosis (Allen et al, 2011;Jiang et al, 2011). LAT, although dispensable to the establishment of latency, does play an active role in silencing HSV-1 lytic gene promoters during establishment of latency in part by facilitating methylation of lysine 9 on histone H3, a post-translational modification indicative of heterochromatin structures (Wang et al, 2005).…”

Section: During Latency Hsv-1 and Vzv Gene Transcription Is Restrictedmentioning

confidence: 99%

“…Due to a non-canonical splice site junction, the 1.5 kb HSV-1 LAT remains as a stable lariat in the neuronal nucleus with a half-life of 24 h (Spivack et al, 1991;Wu et al, 1996;Thomas et al, 2002;Ng et al, 2004). LAT-containing neurons are occasionally surrounded by CD8 + T-cells (Theil et al, 2003a;Verjans et al, 2007) that are primed in the periphery (Held et al, 2012) and LAT functions in part to protect neurons from granzyme B-induced apoptosis (Allen et al, 2011;Jiang et al, 2011). LAT, although dispensable to the establishment of latency, does play an active role in silencing HSV-1 lytic gene promoters during establishment of latency in part by facilitating methylation of lysine 9 on histone H3, a post-translational modification indicative of heterochromatin structures (Wang et al, 2005).…”

mentioning

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

128

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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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Herpes Simplex Virus Infections

Singh

Goodyear

Breuer

2019

Harper's Textbook of Pediatric Dermatology

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The Role of LAT in Increased CD8 ⁺ T Cell Exhaustion in Trigeminal Ganglia of Mice Latently Infected with Herpes Simplex Virus 1

Abstract: Herpes simplex virus (HSV) infection is a classic example of latent viral infection in humans and

Cited by 106 publications

References 82 publications

Interactions between Herpesvirus Entry Mediator (TNFRSF14) and Latency-Associated Transcript during Herpes Simplex Virus 1 Latency

Interactions between Herpesvirus Entry Mediator (TNFRSF14) and Latency-Associated Transcript during Herpes Simplex Virus 1 Latency

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

Herpes Simplex Virus Infections

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The Role of LAT in Increased CD8 + T Cell Exhaustion in Trigeminal Ganglia of Mice Latently Infected with Herpes Simplex Virus 1

Abstract: Herpes simplex virus (HSV) infection is a classic example of latent viral infection in humans and

Cited by 106 publications

References 82 publications

Interactions between Herpesvirus Entry Mediator (TNFRSF14) and Latency-Associated Transcript during Herpes Simplex Virus 1 Latency

Interactions between Herpesvirus Entry Mediator (TNFRSF14) and Latency-Associated Transcript during Herpes Simplex Virus 1 Latency

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

Herpes Simplex Virus Infections

Contact Info

Product

Resources

About

The Role of LAT in Increased CD8 ⁺ T Cell Exhaustion in Trigeminal Ganglia of Mice Latently Infected with Herpes Simplex Virus 1