Tracking the Spread of a
            <i>lacZ</i>
            -Tagged Herpes Simplex Virus Type 1 between the Eye and the Nervous System of the Mouse: Comparison of Primary and Recurrent Infection

Shimeld, C.; Efstathiou, Stacey; Hill, Terry

doi:10.1128/jvi.75.11.5252-5262.2001

Cited by 56 publications

(48 citation statements)

References 44 publications

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“…This is especially significant when it is important to accurately quantify rare events. These same advantages are provided by whole-mount staining of reporter mutants or promoter/reporter-containing transgenic mice, and we and others have found this approach to be useful for certain latency and reactivation studies (16,23,26,37,41). However, the use of promoter reporter mutants as surrogate markers for protein expression requires demonstration that expression of the reporter and the protein coincide.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Analysis of Herpes Simplex Virus Reactivation In Vivo Demonstrates that Reactivation in the Nervous System Is Not Inhibited at Early Times Postinoculation

Sawtell

2003

J Virol

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Recent studies utilizing an ex vivo mouse model of herpes simplex virus (HSV) reactivation have led to the hypothesis that, under physiologic conditions inducing viral reactivation, the immune cells within the infected ganglion block the viral replication cycle and maintain the viral genome in a latent state. One prediction from the ex vivo study is that reactivation in ganglia in vivo would be inhibited at early times postinoculation, when the numbers of inflammatory cells in the ganglia are greatest. To distinguish between an effect of the immune infiltrates on (i) infectious virus produced and/or recovered in the ganglion and (ii) the number of neurons undergoing lytic transcriptional activity (reactivating), an assay to quantify the number of neurons expressing lytic viral protein in ganglia in vivo was developed. Infectious virus and HSV protein-positive neurons were quantified from days 9 through 240 postinoculation in latently infected trigeminal ganglia before and at 22 h after hyperthermic-stress-induced reactivation. Significant increases in the amount of virus and the number of positive neurons were detected poststress in ganglia at all times examined. Unexpectedly, the greatest levels of reactivation occurred at the times examined most proximal to inoculation. Acyclovir was utilized to stop residual acute-phase virus production, and this treatment did not reduce the level of reactivation on day 14. Thus, the virus measured after induction was a product of reactivation. These data indicate that, in contrast to observations in the ex vivo model, immune cells in the ganglia during the resolution of acute infection do not inhibit reactivation of the virus in ganglia in vivo.Herpes simplex virus (HSV) invades the host nervous system during infection at the body surface (7,38,40,44; for a review, see reference 8). In the nervous system, the virus proceeds through the lytic replicative cycle in some neurons, whereas in others lytic-phase transcription is either not initiated or aborted and the viral genome enters a transcriptionally repressed or latent state (see reference 31 for a recent review). These latently infected neurons serve as a lifelong reservoir of viral genetic information within the host. Periodically, in response to stressful stimuli, there is reentry into lytic-phase transcription and infectious virus is produced. This virus is amplified and shed at the surface, either asymptomatically or in association with lesions.In animal models and in humans, HSV reactivation occurs despite an activated competent immune response. Although several potential strategies for immunoevasion by HSV have been identified (discussed in references 1, 19, and 24), which, if any, of these strategies are important for recurrent disease and transmission remains unclear. There is evidence in animal models that augmenting the immune response by specific immunotherapeutic strategies can reduce peripheral disease associated with reactivation (13,14,28,30,47,48). Theoretically, immunotherapeutic strategies could function ...

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Section: Discussionmentioning

confidence: 99%

Quantitative Analysis of Herpes Simplex Virus Reactivation In Vivo Demonstrates that Reactivation in the Nervous System Is Not Inhibited at Early Times Postinoculation

Sawtell

2003

J Virol

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“…The swabs were kept in the culture medium until virus culture. Eye swabs were taken on days 2,4,7,9,12,14,16,18,20,23,25,28 and 34 post infection (p.i). On days 5, 10, 14, 20 and 35 p.i.…”

Section: Experimental Protocolmentioning

confidence: 99%

“…The corneal infection using the HSV-1 strain (F) does not usually lead to clinically manifesting encephalitis in adult BALB/c mice. Viral DNA molecules may, however, be detected in the central nervous system (CNS) of mice [12,14]. The corneal infection of the BALB/c mice does not lead to efficient spontaneous reactivation of HSV to the corneal epithelium.…”

Section: Introductionmentioning

confidence: 99%

Immunomodulation by roquinimex decreases the expression of IL-23 (p19) mRNA in the brains of herpes simplex virus type 1 infected BALB/c mice

Peltoniemi

Broberg

Halenius

et al. 2004

Clinical and Experimental Immunology

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SUMMARYHerpes simplex virus (HSV) is a common neurotropic virus which infects epithelial cells and subsequently the trigeminal ganglia (TG) and brain tissue. We studied how immunomodulation with roquinimex (Linomide®) affects the course of corneal HSV infection in BALB/c mice. BALB/c mice have also been used in a model for HSV-based vectors in treating an autoimmune disease of the central nervous system (CNS). We addressed the questions of how immunomodulation affects the local as well as the systemic immune response and whether roquinimex could facilitate the spread of HSV to the CNS. The cytokine response in the brain and TG was studied using a quantitative rapid real-time RT-PCR method. We were interested in whether immunomodulation affects the expression of the recently described Th1-cytokine IL-23p19 in the brain and TG. The expression of IL-23 mRNA was decreased in brains of roquinimex-treated BALB/c mice. Also the expression of IL-12p35 and IFN-g mRNAs decreased. No significant changes were seen in IL-4 and IL-10 mRNA expression. The cytokine response was also studied using supernatants of stimulated splenocytes by EIA. Roquinimex treatment suppressed the production of IFN-g and also the production of IL-10 in HSV-infected BALB/c mice.

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“…In addition, infectious virus can be isolated from infected nerves when the virus is moving in the anterograde but not the retrograde direction (13,14,15). Glial cells adjacent to infected neurons often are infected, suggesting that mature, infectious, enveloped virions are present in axons during virus egress (29). In contrast, glial cells in a nerve are not infected during virus entry, presumably because the capsid is separated from envelope proteins necessary for membrane fusion during retrograde transport (18).…”

mentioning

confidence: 99%

In Vivo Egress of an Alphaherpesvirus from Axons

Tomishima

Enquist

2002

J Virol

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Many alphaherpesviruses establish a latent infection in the peripheral nervous systems of their hosts. This life cycle requires the virus to move long distances in axons toward the neuron's cell body during infection and away from the cell body during reactivation. While the events underlying entry of the virion into neurons during infection are understood in principle, no such consensus exists regarding viral egress from neurons after reactivation. In this study, we challenged two different models of viral egress from neurons by using pseudorabies virus (PRV) infection of the rat retina: does PRV egress solely from axon terminals, or can the virus egress from axon shafts as well as axon terminals? We took advantage of PRV gD mutants that are not infectious as extracellular particles but are capable of spreading by cell-cell contact. We observed that both wild-type virus and a PRV gD null mutant are capable of spreading from axons to closely apposed nonneuronal cells within the rat optic nerve after intravitreal infection. However, infection does not spread from these infected nonneuronal cells. We suggest that viral egress can occur sporadically along the length of infected axons and is not confined solely to axon terminals. Moreover, it is likely that extracellular particles are not involved in nonneuronal cell infections. Taking these together with previous data, we suggest a model of viral egress from neurons that unifies previous apparently contradictory data.

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Tracking the Spread of a lacZ -Tagged Herpes Simplex Virus Type 1 between the Eye and the Nervous System of the Mouse: Comparison of Primary and Recurrent Infection

Cited by 56 publications

References 44 publications

Quantitative Analysis of Herpes Simplex Virus Reactivation In Vivo Demonstrates that Reactivation in the Nervous System Is Not Inhibited at Early Times Postinoculation

Quantitative Analysis of Herpes Simplex Virus Reactivation In Vivo Demonstrates that Reactivation in the Nervous System Is Not Inhibited at Early Times Postinoculation

Immunomodulation by roquinimex decreases the expression of IL-23 (p19) mRNA in the brains of herpes simplex virus type 1 infected BALB/c mice

In Vivo Egress of an Alphaherpesvirus from Axons

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