Three Herpes Simplex Virus Type 1 Latency-Associated Transcript Mutants with Distinct and Asymmetric Effects on Virulence in Mice Compared with Rabbits

Perng, Guey Chuen; Esmaili, Daniel D.; Slanina, Susan M.; Yukht, Ada; Ghiasi, Homayon; Osório, Nelson; Mott, Kevin R.; Maguen, Barak; Jin, Ling; Nesburn, Anthony B.; Wechsler, Steven L.

doi:10.1128/jvi.75.19.9018-9028.2001

Cited by 40 publications

(49 citation statements)

References 41 publications

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“…If Egr-1 increases HSV-1 replication in cells through repressing LAT, the replication of LAT deletion mutants in cells should be increased compared with that of wild-type viruses. However, our results found that the replication of 2 LAT deletion mutants, dLAT2903 (22) and dlLAT1.8 (23), and their wild-type viruses, McKrae and KOS, was comparable in SK-N-SH cells (data not shown), which is consistent with previous studies using other cell lines (22,23). These results indicate that Egr-1 functions to increase HSV-1 replication in cells in a LAT-independent manner.…”

Section: Egr-1 Activates the Productive Cycle Gene Promoters Of Hsv-1supporting

confidence: 83%

Suppression of transcription factor early growth response 1 reduces herpes simplex virus lethality in mice

Chen¹,

Yao

Chen

et al. 2008

J. Clin. Invest.

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Herpes simplex virus type 1 (HSV-1) infection is the most common cause of sporadic, fatal encephalitis, but current understanding of how the virus interacts with cellular factors to regulate disease progression is limited. Here, we show that HSV-1 infection induced the expression of the cellular transcription factor early growth response 1 (Egr-1) in a human neuronal cell line. Egr-1 increased viral replication by activating promoters of viral productive cycle genes through binding to its corresponding sequences in the viral promoters. Mouse studies confirmed that Egr-1 expression was enhanced in HSV-1-infected brains and that Egr-1 functions to promote viral replication in embryonic fibroblasts. Furthermore, Egr-1 deficiency or knockdown of Egr-1 by a DNA-based enzyme greatly reduced the mortality of HSV-1-infected mice by decreasing viral loads in tissues. This study provides what we believe is the first evidence that Egr-1 increases the mortality of HSV-1 encephalitis by enhancing viral replication. Moreover, blocking this cellular machinery exploited by the virus could prevent host mortality.

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Section: Egr-1 Activates the Productive Cycle Gene Promoters Of Hsv-1supporting

confidence: 83%

Suppression of transcription factor early growth response 1 reduces herpes simplex virus lethality in mice

Chen¹,

Yao

Chen

et al. 2008

J. Clin. Invest.

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“…The HSV-1 LAT locus includes several microRNAs, at least two of which affect expression of a viral protein (54). However, these microRNAs all map outside the first 1.5 kb of the primary 8.3-kb LAT transcript, which is the region of LAT that we previously demonstrated was both sufficient and required for LAT's ability to enhance the reactivation phenotype in mouse or rabbit models of infection (9,55,56). Thus, these microRNAs are unlikely to be involved in enhancing latency/reactivation in these animal models.…”

Section: Discussionmentioning

confidence: 99%

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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“…dLAT2903 contains a deletion from Ϫ161 to ϩ1667 relative to the start of the primary 8.3-kb LAT and thus does not express detectable levels of LAT (48,49). Unlike the wild-type (wt) strain of McKrae, dLAT2903 does not induce high levels of spontaneous reactivation in rabbits (48,49) or high levels of induced reactivation in mice (46). The spontaneous reactivation phenotype of dLAT2903 in rabbits and the explant-induced reactivation phenotype of dLAT2903 in mice are restored to wildtype levels when the first 1.5 kb of LAT (LAT nucleotides 1 to 1499) driven by the LAT promoter is inserted into an ectopic location in the virus.…”

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confidence: 99%

The Locus Encompassing the Latency-Associated Transcript of Herpes Simplex Virus Type 1 Interferes with and Delays Interferon Expression in Productively Infected Neuroblastoma Cells and Trigeminal Ganglia of Acutely Infected Mice

Peng

Henderson

Inman

et al. 2005

J Virol

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The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) is the only abundant viral transcript expressed in latently infected neurons. LAT inhibits apoptosis, suggesting that it regulates latency by promoting the survival of infected neurons. The LAT locus also contains a newly described gene (AL), which is antisense to LAT and partially overlaps LAT encoding sequences. When human (SK-N-SH) or mouse (neuro-2A) neuroblastoma cells were infected with a virus that does not express LAT or AL gene products (dLAT2903), beta interferon (IFN-␤) and IFN-␣ RNA expression was detected earlier relative to the same cells infected with HSV-1 strains that express LAT and AL. Infection of neuro-2A cells with dLAT2903 also led to higher levels of IFN-␤ promoter activity than in cells infected with wild-type (wt) HSV-1. In contrast, IFN RNA expression was the same when human lung fibroblasts were infected with dLAT2903 or wt HSV-1. When BALB/c mice were infected with dLAT2903, IFN-␣ and IFN-␤ RNA expression was readily detected in trigeminal ganglia (TG) 4 days after infection. These transcripts were not detected in TG of mice infected with wt HSV-1 or dLAT2903R (marker-rescued dLAT2903) until 6 days postinfection. When TG single-cell suspensions from infected BALB/c mice were prepared and incubated in vitro with wt HSV-1 as a source of antigen, TG cultures prepared from mice infected with dLAT2903 produced and secreted higher levels of IFN protein than wt HSV-1 or dLAT2903R. Collectively, these studies suggest that the LAT locus interferes with and delays IFN expression.Approximately 90% of adults in the United States are infected with herpes simplex virus type 1 (HSV-1) (38, 72). Recurrent ocular HSV-1 is the leading cause of infectious corneal blindness in industrialized nations (40). HSV-1-induced encephalitis (HSE) is a severe form of focal necrotizing encephalitis that affects at least 2,000 individuals each year in the United States (12,29,71,72). Without antiviral therapy, the mortality rate is as high as 70%; but even with antiviral therapy, 20% of these patients die (59, 60). Although HSE was considered a rare disorder, it is now clear that chemotherapy and perhaps other forms of immunosuppression can lead to HSE and/or bilateral acute retinal necrosis (41). Acute infection is typically initiated in the mucocutaneous epithelium, and then HSV-1 establishes latency in sensory neurons located in trigeminal ganglia (TG) or sacral dorsal root ganglia (20, 68). Despite a vigorous immune response during acute infection, latency is established and periodically reactivates.A single region within the viral long repeats is abundantly transcribed in latently infected neurons, and this transcript is termed the latency-associated transcript (LAT) (6-8, 24, 35, 54, 61, 69, 70). Mice, rabbits, and humans latently infected with HSV-1 express LAT. The primary LAT transcript is approximately 8.3 kb (8,54,75). Splicing of the 8.3-kb transcript yields a stable 2-kb LAT and an unstable 6.3-kb LAT. The 2-kb LAT can also be...

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Three Herpes Simplex Virus Type 1 Latency-Associated Transcript Mutants with Distinct and Asymmetric Effects on Virulence in Mice Compared with Rabbits

Cited by 40 publications

References 41 publications

Suppression of transcription factor early growth response 1 reduces herpes simplex virus lethality in mice

Suppression of transcription factor early growth response 1 reduces herpes simplex virus lethality in mice

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

The Locus Encompassing the Latency-Associated Transcript of Herpes Simplex Virus Type 1 Interferes with and Delays Interferon Expression in Productively Infected Neuroblastoma Cells and Trigeminal Ganglia of Acutely Infected Mice

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