Recurrent Genital Herpes Simplex Virus Infection in Guinea Pigs

Stanberry, Lawrence R.; Kern, Earl R.; Richards, James T.; Overall, James C.

doi:10.1159/000149647

Cited by 62 publications

(35 citation statements)

References 10 publications

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“…We next examined the effect of the LAT substitution mutation on viral infection in a guinea pig model of genital herpes. As is the case in humans, HSV causes acute infections of guinea pigs, establishes latency in sacral ganglia, and reactivates spontaneously to cause recurrent lesions (23,24). In the guinea pig genital model, HSV-2 also recurs significantly more frequently than does HSV-1.…”

Section: Assessment Of La T Substitution In Vivo In Guinea Pigmentioning

confidence: 94%

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 La T Substitution In Vivo In Guinea Pigmentioning

confidence: 94%

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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“…Finally, groups of 10 guinea pigs were inoculated intravaginally with 106 pfu's of each of the four viruses (21)(22)(23). Infection was accomplished by use of virus-soaked cotton tip applicators.…”

Section: Methodsmentioning

confidence: 99%

“…In representative experiments, bilateral trigeminal and sacral-dorsal ganglia were removed from surviving animals. The procedures for virus reactivation and for measurement of latent virus have been previously described (22). Briefly, ganglia were incubated in culture tubes with 1 ml of growth medium for 5-7 d in a CO2 incubator to reactivate latent virus.…”

Section: Methodsmentioning

confidence: 99%

Replication, establishment of latency, and induced reactivation of herpes simplex virus gamma 1 34.5 deletion mutants in rodent models.

Whitley

Kern²,

Chatterjee³

et al. 1993

J. Clin. Invest.

175

146

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“…Animals were examined daily for evidence of recurrent herpetic lesions from day 15 to 92, by an observer uninformed as to treatment group. Nineteen animals were killed 98 to 103 days post-inoculation and their lumbosacral dorsal root ganglia were removed and cocultivated on primary rabbit kidney ceils for the detection of latent virus (Stanberry et al, 1985a). Selected animals were reinoculated on day 100 by intravaginal instillation of 5.7 log10 p.f.u, of HSV-2 strain 333 and evaluated for evidence of reinfection (Stanberry et al, 1986).…”

Section: Methodsmentioning

confidence: 99%

Preinfection Prophylaxis with Herpes Simplex Virus Glycoprotein Immunogens: Factors Influencing Efficacy

Stanberry¹,

Myers²,

Stephanopoulos³

et al. 1989

Journal of General Virology

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SUMMARYUsing a guinea-pig model of genital herpes simplex virus (HSV) infection we explored the protection afforded by preinfection immunization with HSV glycoproteins. Glycoprotein immunogens prepared by recombinant DNA technology were found to be as effective as immunogens purified from HSV-infected cell cultures. Immunized animals developed less severe primary disease and also experienced less frequent recurrent infections. Protection was influenced by both adjuvant and route of administration. These studies suggest that recombinant HSV glycoproteins may be effective immunogens for human clinical trials, but that the development of an effective vaccine will require identification of new potent adjuvants that are safe for human use.

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Recurrent Genital Herpes Simplex Virus Infection in Guinea Pigs

Cited by 62 publications

References 10 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.

Replication, establishment of latency, and induced reactivation of herpes simplex virus gamma 1 34.5 deletion mutants in rodent models.

Preinfection Prophylaxis with Herpes Simplex Virus Glycoprotein Immunogens: Factors Influencing Efficacy

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