Antiviral Therapy of Herpes simplex and Varicella-zoster Virus Infections

Wutzler, Peter

doi:10.1159/000150567

Cited by 71 publications

(50 citation statements)

References 62 publications

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“…We have used a three-dimensional epithelial culture system which promotes the differentiation of human keratinocytes. In HSV-and VZV-infected organotypic epithelial raft cultures, we observed cytopathic changes identical to those found in the squamous epithelium in vivo, including the formation of typical intraepi- Compounds known for their activity against HSV and VZV, e.g., ACV, PCV, BVDU, PFA, and CDV (8,21,28), were tested in monolayers of PHKs and in organotypic epithelial raft cultures. Antiviral assays in monolayers of PHKs, showed that IC 50 values obtained in PHKs were higher than those we have previously reported for human embryonic fibroblasts.…”

Section: Discussionsupporting

confidence: 52%

Organotypic Epithelial Raft Cultures as a Model for Evaluating Compounds against Alphaherpesviruses

Andrei

Oord

Fiten

et al. 2005

Antimicrob Agents Chemother

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The course of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) and varicella-zoster virus (VZV) infections in squamous epithelial cells cultured in a three-dimensional organotypic raft culture was tested. In these raft cultures, normal human keratinocytes isolated from neonatal foreskins grown at the air-liquid interface stratified and differentiated, reproducing a fully differentiated epithelium. Typical cytopathic changes identical to those found in the squamous epithelium in vivo, including ballooning and reticular degeneration with the formation of multinucleate cells, were observed throughout the raft following infection with HSV and VZV at different times after lifting the cultures to the air-liquid interface. Organotypic epithelial "raft" cultures are tissue culture systems that permit full differentiation of keratinocyte monolayers via culturing of the cells on collagen gels at the air-liquid interface. Previously, raft cultures have been successfully applied to the study of human papillomaviruses (6,14), and more recently they have been used for the study of herpes simplex virus (HSV) infection (10,16,24,25) and adeno-associated virus type 2 (15). We have also shown that the organotypic raft culture of human keratinocytes can be used as a model to evaluate both poxvirus replication and efficacy of antiviral agents (22).Skin lesions are frequently induced by viruses and can be the first sign of a systemic disease, particularly in immunocompromised patients and children. Among the dermotropic viruses, skin lesions induced by the alphaherpesviruses herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) and varicella-zoster virus (VZV) show characteristic histologic features.HSV is typically responsible for mucosal lesions of the mouth and genital organs in humans. Following axonal transport, the virus reaches the dorsal root ganglia, where it establishes and maintains lifelong latent infections. Periodically, the virus reactivates, multiplies, and is transported through the axon back to a portal of entry, where it gives characteristic skin lesions (26,27).Primary infection with VZV results in chickenpox (varicella), a common childhood illness. As with other members of the herpesvirus family, infection with VZV is lifelong and the virus enters a latent state following the acute infection (4). Latency is associated with persistence of the viral DNA in the posterior root ganglia, and reactivation of the virus results in skin lesions characteristic of herpes zoster (shingles). Herpes zoster manifests as a localized rash in a unilateral, dermatomal distribution that is often associated with severe neuropathic pain (11,23).As keratinocytes are the main target cells for productive infection in vivo for both HSV and VZV, characterization of virus replication in organotypic raft cultures of these cells represents a very relevant model for studying virus-host cell interactions and antiviral agents. Here we report the infection of epithelial raft cultures with HSV and VZV, the lesions observed in these cultures...

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Section: Discussionsupporting

confidence: 52%

Organotypic Epithelial Raft Cultures as a Model for Evaluating Compounds against Alphaherpesviruses

Andrei

Oord

Fiten

et al. 2005

Antimicrob Agents Chemother

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“…However, differences of less or comparable magnitude are regarded as both biologically and clinically significant in a variety of clinical studies of new antiviral drugs against herpes. 10,11,[39][40][41][42][43][44][45] Thus, the difference between 23% reactivation in COX-2-treated mice compared to 54% in control, untreated mice seen in our study is biologically and likely clinically significant if translated to humans. It may be that a combination of an antiviral drug, such as acyclovir, and celecoxib, a COX-2 inhibitor, would either additively or synergistically enhance the level of inhibition of viral reactivation.…”

Section: Discussionmentioning

confidence: 56%

Inhibition of Cyclooxygenase 2 Synthesis SuppressesHerpes simplexVirus Type 1 Reactivation

Gebhardt

Varnell

Kaufman

2005

Journal of Ocular Pharmacology and Therapeutics

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Recurrent herpes virus infection, in which the virus reactivates from the nervous system and causes painful lesions in peripheral tissues, is a significant clinical problem. Our recent studies showing that the amount of cyclooxygenase 2 (COX-2) in the trigeminal ganglia of heat-stressed untreated mice is higher than the amount in heat-stressed mice treated with the COX-2 inhibitor, celecoxib, have indicated that the prostaglandin synthesis pathway--and in particular COX-2--may be an intermediate in the pathway to herpes viral reactivation. To further study this process, we infected the corneas of mice using topical application to a lightly scratched epithelium and waited 30 days for Herpes simplex virus type 1 (HSV-1) latency to be established in the trigeminal ganglia. Prior to the induction of viral reactivation, the mice were treated orally with celecoxib. Treated and untreated mice were induced to undergo reactivation by immersion in 43 degrees C water for 10 min. The shedding of virus at the ocular surface was determined by culturing ocular swabs with indicator cells. The presence of infectious virus in the trigeminal ganglion was evaluated by incubating ganglion homogenates with indicator cells and observing for cytopathic effect. Celecoxib treatment significantly suppressed viral reactivation when given prophylactically by the gastrointestinal route. The numbers of corneas and ganglia containing infectious virus were significantly lower in the celecoxib-treated animals, compared to the placebo-treated mice. These experiments demonstrate that a selective COX-2 inhibitor can suppress hyperthermic stress-induced herpes viral reactivation in the nervous system. It may be possible to use COX-2 inhibitors to prevent viral reactivation in high-risk patients by drug prophylaxis.

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“…Enzephalitiden werden bei immunsupprimierten Patienten häufig beobachtet. Da mit den Nukleosidanaloga Aciclovir, Brivudin, Famciclovir und Valaciclovir mehrere wirksame Virostatika für die Behandlung des Zosters zur Verfügung stehen [21], ist eine schnelle und sichere Diagnosestellung von zunehmender Bedeutung. Darüber hinaus können bei frühzeitigem Therapiebeginn spätere Komplikationen, insbesondere die PZN, zum Teil verhindert werden [11].…”

Section: Besprechungunclassified