Regulation of Caspase 8- and Caspase 9-Induced Apoptosis by the Herpes Simplex Virus Type 1 Latency-Associated Transcript

Henderson, Gail; Peng, Weiping; Jin, Ling; Perng, Guey Chuen; Nesburn, Anthony B.; Wechsler, Steven L.; Jones, Clinton

doi:10.1080/13550280290101085

Cited by 90 publications

(76 citation statements)

References 70 publications

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“…More recently, we showed that a plasmid expressing LAT can block apoptosis induced by either caspase 8 or caspase 9 (Henderson et al, 2002;Jin et al, 2003). Thus, LAT appears capable of interfering with both major apoptotic pathways.…”

Section: Discussionmentioning

confidence: 99%

The bovine herpesvirus-1 LR ORF2 is critical for this gene's ability to restore the high wild-type reactivation phenotype to a herpes simplex virus-1 LAT null mutant

Mott

Osório

Jin

et al. 2003

Journal of General Virology

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The bovine herpesvirus-1 LR ORF2 is critical for this gene's ability to restore the high wild-type reactivation phenotype to a herpes simplex virus-1 LAT null mutant During neuronal latency of herpes simplex virus (HSV)-1, the latency-associated transcript (LAT) is the only viral gene readily detectable. LAT is required for the high-level reactivation phenotype in animal models. LAT's anti-apoptotic activity was recently demonstrated by our group and it was proposed that LAT's anti-apoptotic function is involved in enhancing the reactivation phenotype. Recently, using chimeric virus CJLAT, it was shown that the reactivation phenotype of LAT " mutant dLAT2903 can be restored to wild-type levels by inserting the bovine herpes virus (BHV)-1 latency-related (LR) gene into the LAT locus of this HSV-1 LAT deletion mutant. Although transcription of the LR gene, like LAT, inhibits apoptosis, LR appears to be multifunctional. To investigate whether the LR gene's anti-apoptotic function was responsible for restoring the high-reactivation phenotype, a mutated BHV-1 LR gene was inserted into the LAT locus of HSV-1 generating the chimeric virus CJLATmut. This mutation consists of three stop codons inserted just after the ATG of the first LR open reading frame (ORF2). In plasmids and in a BHV-1 mutant, this mutation eliminated the LR gene's anti-apoptotic activity, strongly suggesting that ORF2 encodes a protein responsible for LR's anti-apoptotic activity. Reactivation of the CJLATmut virus, in both rabbits and mice, was significantly lower than in wild-type McKrae virus (P=0?0001 and P=0?0003, respectively) and CJLAT virus, containing wild-type LR in place of LAT (P<0?0001) and was similar to LAT " dLAT2903 (P=0?8 and P=0?7, respectively). Thus, disruption of BHV-1 LR ORF2 eliminated the high-reactivation phenotype. INTRODUCTIONOver 80 % of adults in the United States harbour latent herpes simplex virus type 1 (HSV-1). Following primary peripheral infection of the eye, HSV-1 travels along axons via antegrade transport to sensory neurons of the trigeminal ganglia (TG) where latency is established. The latent virus reactivates sporadically as a result of stress, UV exposure and other unknown stimuli. Reactivations can also occur in the absence of known stimuli, which we have operationally defined as spontaneous reactivation. Following reactivation, HSV-1 travels along axons in a retrograde direction to the initial infection site, where it can replicate and cause recurrent disease (Andreansky et al., 1998;Roizman & Whitley, 2001). Recurrent HSV-1 infection in the eye can cause corneal scarring leading to the loss of vision. As a result, HSV-1 is one of the leading infectious causes of corneal blindness in the developed world (Liesegang et al., 1989). The mechanism(s) by which the latent virus reactivates and causes disease are currently not completely understood.The only gene that is actively transcribed during HSV-1 neuronal latency is the latency-associated transcript (LAT) (Rock et al., 1987b; Stevens et al., 1987). A stab...

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Section: Discussionmentioning

confidence: 99%

The bovine herpesvirus-1 LR ORF2 is critical for this gene's ability to restore the high wild-type reactivation phenotype to a herpes simplex virus-1 LAT null mutant

Mott

Osório

Jin

et al. 2003

Journal of General Virology

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“…LAT inhibits apoptosis in transiently transfected cells and TG of infected rabbits and mice (Ahmed et al, 2002;Inman et al, 2001;Kang et al, 2003;Perng et al, 2000) and can inhibit caspase 3 activation (Carpenter et al, 2007). Consequently, LAT can inhibit caspase 8-or caspase 9-induced apoptosis (Henderson et al, 2002;Jin et al, 2003;Peng et al, 2004), the two major apoptotic pathways (Krueger et al, 2001;Schmitz et al, 2000;Wang, 2001). The anti-apoptosis functions of LAT correlate with promoting spontaneous reactivation (Inman et al, 2001;Jin et al, 2003) and appear to be the crucial function of LAT because three different anti-apoptosis genes restore wt levels of spontaneous reactivation to a LAT null mutant virus (Jin et al, 2005(Jin et al, , 2008Mott et al, 2003;Perng et al, 2002b).…”

Section: Introductionmentioning

confidence: 99%

Herpes simplex virus type 1 latency-associated transcript inhibits apoptosis and promotes neurite sprouting in neuroblastoma cells following serum starvation by maintaining protein kinase B (AKT) levels

Carpenter

Hsiang

et al. 2009

Journal of General Virology

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The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) is expressed abundantly in latently infected sensory neurons. LAT-deletion-mutant virus strains have reducedreactivation phenotypes in small animal models of infection, demonstrating that LAT plays an important role in the latency-reactivation cycle of HSV-1. Previous studies demonstrated that the anti-apoptosis functions of LAT are important for regulating the latency-reactivation cycle because three different anti-apoptosis genes can substitute for LAT. Although LAT inhibits caspase 3 activation, the signalling pathway by which LAT inhibits caspase 3 activation was not identified. In this study, we analysed mouse neuroblastoma cells (C1300) that express LAT stably (DC-LAT6 cells) following serum starvation. As expected, DC-LAT6 cells were resistant to apoptosis following serum withdrawal. Levels of total and phosphorylated AKT (protein kinase B), a serine/threonine protein kinase that promotes cell survival, were higher in DC-LAT6 cells after serum withdrawal than in C1300 cells or a cell line stably transfected with a LAT promoter mutant (DC-DLAT311). A specific AKT inhibitor reduced the anti-apoptosis functions of LAT and phosphorylated AKT levels. After serum withdrawal, more DC-LAT6 cells sprouted neurites and exhibited a differentiated morphology. NeuN (neuronal nuclei), a neuron-specific nuclear protein, was expressed abundantly in DC-LAT6 cells, but not C1300 cells, after serum withdrawal, further supporting the concept that LAT enhanced neuronal-like morphology. Collectively, these studies suggested that LAT, directly or indirectly, maintained total and phosphorylated AKT levels, which correlated with increased cell survival and mature neuronal-like morphology.

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“…The ability of LAT to interfere with apoptosis correlates with its ability to promote spontaneous reactivation (16,19), suggesting the antiapoptotic activity of LAT has biological significance. Recent studies have demonstrated that LAT-expressing plasmids inhibit caspase 8-and caspase 9-induced apoptosis (14,19). In the context of the viral genome, LAT promotes neuronal survival in TG of infected rabbits (45) and in acutely infected mice (1).…”

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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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Regulation of Caspase 8- and Caspase 9-Induced Apoptosis by the Herpes Simplex Virus Type 1 Latency-Associated Transcript

Cited by 90 publications

References 70 publications

The bovine herpesvirus-1 LR ORF2 is critical for this gene's ability to restore the high wild-type reactivation phenotype to a herpes simplex virus-1 LAT null mutant

The bovine herpesvirus-1 LR ORF2 is critical for this gene's ability to restore the high wild-type reactivation phenotype to a herpes simplex virus-1 LAT null mutant

Herpes simplex virus type 1 latency-associated transcript inhibits apoptosis and promotes neurite sprouting in neuroblastoma cells following serum starvation by maintaining protein kinase B (AKT) levels

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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