Zosteriform Spread of Herpes Simplex Virus Type 2 Genital Infection in the Guinea-pig

Bernstein, David I.; Stanberry, Lawrence R.

doi:10.1099/0022-1317-67-9-1851

Cited by 17 publications

(6 citation statements)

References 16 publications

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“…By 12 to 14 days the clinical effects of primary infection have subsided, infectious virus cleared and latent infection established. It is probable that a similar course of events occurs in humans infected with HSV [4,7,29,36]. Therefore, since active virus replication may occur at a number of points in vivo, vaccination could interfere with establishment of latency by enhancing immune responses at these points.…”

Section: Discussionmentioning

confidence: 95%

“…Studies in experimental animals indicate that a number of stages can be recognised during primary infection with HSV and the establishment of latency [4,5,17,43,46]. Although studies with mutant viruses have suggested that virus replication may not be essential for establishment of latency in vivo [45], in most natural and experimental infections with wild type viruses, the first stage is a period of local replication at the inoculation site.…”

Section: Discussionmentioning

confidence: 99%

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Acute and latent infection of mice immunised with HSV-1 ISCOM vaccine

Ertürk

Hill

Shimeld³

et al. 1992

Archives of Virology

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The effect of immunisation with an HSV-1 antigen preparation (containing at least 6 viral glycoproteins) on primary infection with HSV and the establishment of latency, was assessed in two mouse models (involving either skin or corneal challenge with virus). The vaccine preparation, given either with Freund's complete adjuvant or aluminium hydroxide gel or in the form of immunostimulating complexes (ISCOMS), induced high ELISA antibody responses (highest with HSV as the ISCOM preparation) and low levels of neutralising antibody. In both models, immunisation with the HSV ISCOM preparation significantly reduced the incidence of zosteriform spread of virus and the severity of disease and, in some cases, the incidence of latent infection in sensory ganglia. In the eye model it was possible to show that immunisation with the HSV ISCOMS restricted the establishment of latency almost entirely to the ophthalmic part of the trigeminal ganglion. Protection from establishment of latency correlated with prechallenge antibody levels.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Acute and latent infection of mice immunised with HSV-1 ISCOM vaccine

Ertürk

Hill

Shimeld³

et al. 1992

Archives of Virology

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“…Similarly, the delayed and decreased dose reduced recurrent disease, but to a lesser extent than earlier and higher dosing did. Since HSV enters peripheral nerves and infects dorsal root ganglia at about 2 to 3 days after genital inoculation of guinea pigs (3,26), it is not surprising that delayed therapy was somewhat less effective in reducing recurrences than was treatment that was begun prior to ganglionic involvement. It appeared, however, that therapy that was begun even 36 h after viral inoculation decreased latent infection, because we observed significant differences in the recovery of latent virus from R837 recipients versus that from placebo recipients, and latent virus was only recovered from R837 recipients when HMBA was added to the explant culture.…”

Section: Discussionmentioning

confidence: 99%

Effects of the immunomodulating agent R837 on acute and latent herpes simplex virus type 2 infections

Bernstein

Harrison

1989

Antimicrob Agents Chemother

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R837 is an immune modulator with no in vitro activity against herpes simplex virus (HSV). We evaluated topical R837 as therapy for genital HSV type 2 infection using the guinea pig model of this disease. Furthermore, we investigated the effect of R837 therapy on acute and latent neural HSV infections. Therapy initiated 12 h after viral inoculation and given twice a day significantly reduced the acute neural infection so that HSV was recovered from only 1 of 64 neural tissue specimens obtained from R837 recipients compared with 43 of 56 specimens obtained from placebo recipients (P < 0.0001). R837 initiated 36 h after HSV inoculation and given once a day also significantly reduced the total mean lesion score of the acute disease from 14.1 ± 4.3 to 2.6 ± 5.3 (P < 0.0001) and shortened the period of vaginal HSV shedding from 6.9 ± 1.7 to 3.2 --1.4 days (P < 0.001). R837-treated animals also developed fewer HSV recurrences than did controls (2.0 ± 1.7 versus 5.1 ± 1.7; P < 0.0002). Latent HSV was detected in 23 of 24 dorsal root ganglia explant cultures from placebo recipients but in only 2 of 30 cultures from R837-treated animals, and HSV in these 2 cultures was detectable only with the addition of a demethylating agent. Topical R837 exhibited in vivo anti-HSV activity, reducing both acute and latent neural infections as well as acute and recurrent genital disease.Therapy for herpes simplex virus (HSV) infections should moderate the acute phase of disease, the development of latency, and the frequency of recurrences. Most antiviral agents modify the acute phase of clinical disease but have no effect on latent virus unless therapy is initiated within a few hours of HSV inoculation (13,14,17,18,23). For example, in the guinea pig model of genital HSV type 2 (HSV-2) infection, acyclovir decreased the initial disease incidence but did not alter the establishment of latency or recurrence rates, even when therapy was initiated within 12 h of HSV-2 inoculation (4). In contrast, we have observed significant decreases in both detectable latent virus and genital recurrences after administration of topical R837 was begun 12 h after HSV-2 inoculation (16).R837 is a biologic response modifier that has no in vitro anti-HSV activity (16). R837 induces interferon when administered either intraperitoneally (8) or intravaginally (16) and enhances HSV-specific lymphocyte proliferation, interleukin-2 production, and delayed hypersensitivity but not antibody production (16). Because the decreased recurrence rate that we previously observed could have been due to persisting up-regulation of cell-mediated immunity, decreased neural HSV-2 levels, or both, we examined the effects of R837 therapy administered as described previously (16) on the magnitude of initial neural infection and sought latent virus by methods which increase the in vitro reactivation of latent virus (2).In previous studies, R837 administered twice a day at 10 mg/kg per day induced fever, weight loss, and decreased water intake. In addition, 35% of R837-treated animals...

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“…These findings are consistent with previous findings in the guinea pig model of vaginal HSV-2 infection as well as with studies of human sacral ganglia which indicate HSV-2 latency is widespread. Bernstein and Stanberry performed a detailed analysis of primary vaginal HSV-2 infection in the guinea pig and found that HSV-2 was detected from ipsilateral dorsal root ganglia on days 2 and 3 postinfection and from contralateral dorsal root ganglia on days 4 and 5 and that the majority (9/12) of animals shed virus on the contralateral genital skin from the initially infected ganglion (28), suggesting that HSV-2 infection can spread throughout neuronal tissues. Although data on the distribution of HSV-2 in human sacral ganglia are limited, Obara et al described PCR and in situ hybridization evidence of widespread sacral ganglion infection in three persons coinfected with HSV-1 and HSV-2, with HSV-2 detected in 21 of 23 sacral ganglia and HSV-1 in 22 of 23 ganglia (29), and concluded that both HSV-1 infection and HSV-2 infection are latent bilaterally throughout the sacral ganglia.…”

Section: Discussionmentioning

confidence: 99%

Virologic and Immunologic Evidence of Multifocal Genital Herpes Simplex Virus 2 Infection

Johnston

Zhu

Jing

et al. 2014

J Virol

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Genital herpes simplex virus (HSV) reactivation is thought to be anatomically and temporally localized, coincident with limited ganglionic infection. Short, subclinical shedding episodes are the most common form of HSV-2 reactivation, with host clearance mechanisms leading to rapid containment. The anatomic distribution of shedding episodes has not been characterized. To precisely define patterns of anatomic reactivation, we divided the genital tract into a 22-region grid and obtained daily swabs for 20 days from each region in 28 immunocompetent, HSV-2-seropositive persons. HSV was detected via PCR, and sites of asymptomatic HSV shedding were subjected to a biopsy procedure within 24 h. CD4؉ and CD8 ؉ T cells were quantified by immunofluorescence, and HSV-specific CD4 ؉ T cells were identified by intracellular cytokine cytometry. HSV was detected in 868 (7%) of 11,603 genital swabs at a median of 12 sites per person (range, 0 to 22). Bilateral HSV detection occurred on 83 (67%) days with shedding, and the median quantity of virus detected/day was associated with the number of sites positive (P < 0.001). In biopsy specimens of asymptomatic shedding sites, we found increased numbers of CD8 ؉ T cells compared to control tissue (27 versus 13 cells/mm 2 , P ‫؍‬ 0.03) and identified HSV-specific CD4 ؉ T cells. HSV reactivations emanate from widely separated anatomic regions of the genital tract and are associated with a localized cellular infiltrate that was demonstrated to be HSV specific in 3 cases. These data provide evidence that asymptomatic HSV-2 shedding contributes to chronic inflammation throughout the genital tract. IMPORTANCEThis detailed report of the anatomic patterns of genital HSV-2 shedding demonstrates that HSV-2 reactivation can be detected at multiple bilateral sites in the genital tract, suggesting that HSV establishes latency throughout the sacral ganglia. In addition, genital biopsy specimens from sites of asymptomatic HSV shedding have increased numbers of CD8 ؉ T cells compared to control tissue, and HSV-specific CD4 ؉ T cells are found at sites of asymptomatic shedding. These findings suggest that widespread asymptomatic genital HSV-2 shedding is associated with a targeted host immune response and contributes to chronic inflammation throughout the genital tract. H erpes simplex virus 2 (HSV-2) infects over 500 million people worldwide (1) and is the leading cause of genital ulcer disease (2) and increases the risk of HIV acquisition (3). Herpetic genital ulcers in the immunocompetent person are localized with respect to time and anatomic site (4), consistent with reactivation of virus from the ganglion innervating this region. However, most HSV genital shedding is subclinical, with rapid onset and clearance (5, 6). Such subclinical reactivation may be more widespread in the genital area (7), consistent with frequent leakage of virus into the genital skin and mucosa with localized host containment (8, 9). Mathematical models suggest that observed shedding patterns are the result of ove...

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Zosteriform Spread of Herpes Simplex Virus Type 2 Genital Infection in the Guinea-pig

Cited by 17 publications

References 16 publications

Acute and latent infection of mice immunised with HSV-1 ISCOM vaccine

Acute and latent infection of mice immunised with HSV-1 ISCOM vaccine

Effects of the immunomodulating agent R837 on acute and latent herpes simplex virus type 2 infections

Virologic and Immunologic Evidence of Multifocal Genital Herpes Simplex Virus 2 Infection

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