Herpes simplex virus latent phase transcription facilitates in vivo reactivation

Hill, James M.; Sedarati, Farhad; Javier, Ronald T.; Wagner, Edward K.; Stevens, Jack G.

doi:10.1016/0042-6822(90)90060-5

Cited by 264 publications

(240 citation statements)

References 20 publications

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“…The rabbit ocular model o f HSV-1 infection mimics natural human infection with HSV-1. The virus causes acute ocular infections, establishes latency in trigeminal ganglia, and can be induced to reactivate by appropriate stimuli (14). Also similar to human infections, HSV-2 does not reactivate well in vivo from rabbit trigeminal ganglia.…”

Section: Assessment Of L/it Subsitution In Vivo In Rabbit Eyesmentioning

confidence: 99%

“…In previous experiments, deletions in the LAT region did not influence establishment or maintenance of viral latency in rabbits (14) and guinea pigs (18), although it did in mice (20). Previous studies in which latent virus was recovered in tissue culture from explanted guinea pig sacral ganglia also showed no difference between recovery of la- tent HSV-1 or HSV-2.…”

Section: Assessment Of the La T Region Substitutions On Establmlment mentioning

confidence: 99%

“…The more abundant nuclear LAT introns (2.2 kbp in HSV-2 [3][4][5], 2.0 kbp and 1.5 kbp in HSV-1 [6][7][8][9]) are processed via a splicing mechanism from less stable ~8.5-kbp primary LAT transcripts (10). The LATs of HSV-1 and HSV-2 (11)(12)(13) are required for efficient reactivation from latency in vivo, but have not been shown to influence acute replication of virus or establishment of latency (14)(15)(16)(17)(18)(19) in most 1Abbreviations used in this paper: HSV-1 and HSV-2, herpes simplex virus type 1 and 2; LAT, latency-associated transcript; PI postinoculation; PRK, primary rabbit kidney. animal models, although there is some evidence suggesting an effect on establishment of latency in a mouse model of infection with HSV-1 (20).…”

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The characteristic site-specific reactivation phenotypes of HSV-1 and HSV-2 depend upon the latency-associated transcript region.

Yoshikawa

Hill

Stanberry

et al. 1996

The Journal of Experimental Medicine

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SummaryAfter replication at sites of initial inoculation, herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) establish lifelong latent infections of the sensory and autonomic neurons of the ganglia serving those sites. Periodically, the virus reactivates from these neurons, and travels centripetally along the neuronal axon to cause recurrent epithelial infection. The major clinically observed difference between infectious with herpes simplex virus type 1 and type 2 is the anatomic site specificity of recurrence. HSV-1 reactivates most efficiently and frequently from trigeminal ganglia, causing recurrent ocular and oral-facial lesions, while HSV-2 reactivates primarily from sacral ganglia causing recurrent genital lesions. An intertypic recombinant virus was constructed and evaluated in animal models of recurrent ocular and genital herpes. Substitution of a 2.8-kbp region from the HSV-1 latency-associated transcript (LAT) for native HSV-2 sequences caused HSV-2 to reactivate with an HSV-1 phenotype in both animal models. The HSV-2 phenotype was restored by replacing the mutated sequences with wild-type HSV-2 LAT-region sequences. These sequences or their products must act specifically in the cellular environments of trigeminal and sacral neurons to promote the reactivation patterns characteristic of each virus. p primary or initial infections with herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) ~ are clinically indistinguishable. While social habits and other factors contribute to varying sites of initial infections, the predilection of virus to reactivate from specific ganglionic sites maintains the well-known associations of HSV-2 with genital herpes and of HSV-1 with ocular and oral-facial herpes (1, 2). The HSV latency-associated transcripts (LATs) are a family of transcripts specified by the genomic long repeat regions. The more abundant nuclear LAT introns (2.2 kbp in HSV-2 [3-5], 2.0 kbp and 1.5 kbp in HSV-1 [6-9]) are processed via a splicing mechanism from less stable ~8.5-kbp primary LAT transcripts (10). The LATs of HSV-1 and HSV-2 (11-13) are required for efficient reactivation from latency in vivo, but have not been shown to influence acute replication of virus or establishment of latency (14-19) in most 1Abbreviations used in this paper: HSV-1 and HSV-2, herpes simplex virus type 1 and 2; LAT, latency-associated transcript; PI postinoculation; PRK, primary rabbit kidney. animal models, although there is some evidence suggesting an effect on establishment of latency in a mouse model of infection with HSV-1 (20). The sequences of the LAT regions differ significantly between HSV-1 and HSV-2 (4, 21, 22), leading to the hypothesis that differences in the LATs could be responsible for site-specificity of virus recurrence. To test this hypothesis, we introduced an alteration into HSV-2 strain 333 that substituted the LAT region from HSV-1 strain 17syn+ for native HSV-2 LAT sequences, and constructed a rescuant of this mutant. We then tested the ability of parent, mutant, and rescuant viruses to replic...

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Section: Assessment Of L/it Subsitution In Vivo In Rabbit Eyesmentioning

confidence: 99%

Section: Assessment Of the La T Region Substitutions On Establmlment mentioning

confidence: 99%

mentioning

confidence: 99%

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The characteristic site-specific reactivation phenotypes of HSV-1 and HSV-2 depend upon the latency-associated transcript region.

Yoshikawa

Hill

Stanberry

et al. 1996

The Journal of Experimental Medicine

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“…Approximately one-third of the latently infected neurons express high levels of a single transcript, termed the latency-associated transcript (LAT) (12,18). This transcript is important for reactivation, even though LAT does not seem to encode a protein (14,17).While LAT is required for efficient reactivation in animal models, its mechanism is not well understood. One factor that complicates these analyses is that observations vary depending on the animal model (24) and HSV strain (20, 28) used.…”

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confidence: 99%

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confidence: 99%

Wide Variations in Herpes Simplex Virus Type 1 Inoculum Dose and Latency-Associated Transcript Expression Phenotype Do Not Alter the Establishment of Latency in the Rabbit Eye Model

O'Neil

Loutsch

Aguilar

et al. 2004

J Virol

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The latency-associated transcript (LAT) is required for efficient reactivation of herpes simplex virus type 1 from latent infection in the rabbit eye model, but LAT's mechanism of action is unknown. In addition to reactivation, the LAT region seems to correspond to multiple functions, with some LAT deletion mutants exhibiting increased virulence, increased neuronal death, and restricted establishment of latency. While a LAT promoter deletion mutant (17⌬Pst) seems to be primarily restricted in reactivation in the rabbit, subtle effects on virulence or the establishment of latency cannot be precluded at the normal high levels of virus inoculum used in the rabbit model. Since such additional LAT phenotypes may be more evident with lower doses of virus, we evaluated the influence of initial viral inoculum and LAT expression on the progression of acute infection and the establishment of latency. We have assayed both virus recovery rates and viral genome loads in rabbit corneas and trigeminal ganglia. Our results show that (i) in the corneas and trigeminal ganglia, the maximum amount of virus present during acute infection is independent of the LAT genotype and inoculum dose, although greater viral yields are obtained earlier with higher inoculum doses, and (ii) the range in numbers of latent genomes detected in the ganglia is independent of the inoculum dose and the LAT genotype and therefore no difference in establishment of latency is observed.Herpes simplex virus type 1 (HSV-1) establishes latency in neurons of sensory ganglia innervating the site of initial infection. The virus can reactivate spontaneously or under conditions of stress to cause a recurrent infection. During latency, the genome forms an episome in neuronal nuclei from which no viral replication occurs (19,26). Approximately one-third of the latently infected neurons express high levels of a single transcript, termed the latency-associated transcript (LAT) (12,18). This transcript is important for reactivation, even though LAT does not seem to encode a protein (14,17).While LAT is required for efficient reactivation in animal models, its mechanism is not well understood. One factor that complicates these analyses is that observations vary depending on the animal model (24) and HSV strain (20, 28) used. The two most common models employed are the rabbit and mouse. In the rabbit eye model, latency is established in trigeminal ganglia (TG) following corneal inoculation. Reactivation, either spontaneous or induced by iontophoresis of epinephrine, is scored by recovery of infectious virus in the tear film (1,13,21). In the mouse model, latency is established in the trigeminal or dorsal root ganglia following inoculation of corneas or rear footpads, respectively. Viral reactivation from ganglia can be induced by thermal stress, as demonstrated by the presence of infectious virus in the ganglia, or by explant cocultivation of dissected ganglia on cultured cells (30,32).Mutants with large LAT deletions have been reported to have reduced numbers of latent v...

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Cell response to herpes simplex virus type 1 infection mediated by biphasic calcium-phosphate ceramics:In vitro approach

Varadinova

Zlateva

Dyulgerova

2001

J. Biomed. Mater. Res.

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Based on well-documented data showing that bioactive ions (such as Ca2+, PO4-, etc.) released by BCPC induce various cell responses and on the significance of herpes outbreaks in human pathology, we investigated whether BCPC can modify cell response to HSV-1 infection. The roles of some physical and chemical properties of ceramics were evaluated using three BCPC samples--French commercial macro-microporous (FR) and two Bulgarian microporous laboratory samples--one of which was modified with magnesium (BG and BG + Mg). Samples only washed in 0.9% NaCl were designated as nonconditioned while those resuspended in cell growth medium for 10 days after washing were designated as conditioned. Experiments were done on cells from the continuous MDBK line precultured on BCPC surfaces for different time intervals and thereafter HSV-1 infected. The yield of infectious virus progeny, measured as virus titers, was the parameter used to determine the cell response to HSV-1 infection mediated by BCPC as compared to that of the virus control, that is, virus yield in cells cultured without BCPC. The data obtained show that all three nonconditioned BCPC samples were able to modify cells to resist HSV-1 infection. The prolongation of the resistant state depended on the specific physical and chemical properties of the particular BCPC sample: as the data show that the conditioning procedure (1) increased the ability of BG + Mg to promote cell resistance, and (2) reduced the ability of FR samples to modify cells to resist HSV-1 infection. The data obtained show that apart from Ca2+ and PO4-, ions of biometals such as Mg2+ also are responsible for the induction and maintenance of cell resistance to HSV-1 infection.

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Herpes simplex virus latent phase transcription facilitates in vivo reactivation

Cited by 264 publications

References 20 publications

The characteristic site-specific reactivation phenotypes of HSV-1 and HSV-2 depend upon the latency-associated transcript region.

The characteristic site-specific reactivation phenotypes of HSV-1 and HSV-2 depend upon the latency-associated transcript region.

Wide Variations in Herpes Simplex Virus Type 1 Inoculum Dose and Latency-Associated Transcript Expression Phenotype Do Not Alter the Establishment of Latency in the Rabbit Eye Model

Cell response to herpes simplex virus type 1 infection mediated by biphasic calcium-phosphate ceramics:In vitro approach

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