Chronic Ulcerating Acyclovir-Resistant Varicella Zoster Lesions in an AIDS Patient

Bernhard, Peter; Obel, Niels

doi:10.3109/00365549509047078

Cited by 16 publications

(20 citation statements)

References 18 publications

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“…Varicella and zoster are treated with acyclovir and its derivatives, but pain and other sequelae often persist despite therapy (42,49). In addition, there are reports of acyclovir-resistant VZV arising during long-term treatment for chronic zoster in immune-deficient patients (4,8,30). Resistance to antiviral agents that target cellular genes is unlikely to arise by mutations in the virus genome, so cdk inhibitors such as Rosco would have that advantage if they were developed as new treatments for VZV infections.…”

Section: Discussionmentioning

confidence: 99%

Roscovitine, a Cyclin-Dependent Kinase Inhibitor, Prevents Replication of Varicella-Zoster Virus

Taylor

Kinchington

Cuba

et al. 2004

J Virol

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Understanding the interactions between varicella-zoster virus (VZV) and host cells can be addressed by using small molecule inhibitors of cellular enzymes. Roscovitine (Rosco) is a purine derivative that inhibits cyclindependent kinase 1 (cdk1), cdk2, cdk5, cdk7, and cdk9, which are key regulators of the cell cycle and transcription. Herpesviruses are known to interact with cell cycle proteins; thus, the antiviral effects of Rosco on VZV growth were evaluated. In a plaque reduction assay, 25 M Rosco prevented VZV replication, and the antiviral effect was reversible for at least up to 24 h posttreatment. Rosco also reduced expression of the major transactivator, IE62, over 48 h. Confocal microscopy studies indicated that Rosco caused the immediate-early proteins ORF4 and IE62 to abnormally localize in infected cells and prevented cell-cell spread of VZV over 48 h. Rosco was found to inhibit VZV DNA synthesis as measured by real-time PCR, and this technique was used to estimate the 50% effective concentration (EC 50 ) of 14 M. This value was close to the EC 50 estimate of 12 M determined from plaque reduction assays. At 25 M, Rosco was not cytotoxic over 48 h in a neutral red uptake assay, and proliferation was slowed as the cells accumulated in a G 2 -like state. These results demonstrate the importance of cdk's in VZV replication and suggest that cdk inhibitors could serve as useful VZV antivirals.During primary infection, varicella-zoster virus (VZV), a human-restricted alphaherpesvirus, is carried within T cells to epithelial cells and neurons, resulting in the characteristic vesicular rash of varicella (chicken pox). Following recovery of the host, VZV establishes lifelong latency in sensory neurons. Reactivation from ganglia occurs in some 20% of the population, leading to resumed VZV replication in the skin, giving rise to the unilateral distribution of zoster (shingles). As such, the course of human infection requires VZV replication in a variety of host cell types that are dividing (basal keratinocytes), quiescent (memory T cells and dermal fibroblasts), and terminally differentiated (neurons) (1,27). Although the molecular basis of VZV tissue tropism is not completely understood, the ability to grow in this wide host cell range relies upon expression of specific viral proteins that likely play important roles in infection. For example, when recombinant VZV mutant strains were created that did not express either of two viral kinases, open reading frame 47 (ORF47) or ORF66, there was no effect on viral replication in MeWo cells whatsoever. Yet the kinase ORF47 was essential in skin and T cells in the SCID-hu mouse model and in T cells grown in culture, whereas the viral kinase encoded by ORF66 was important for full infectivity in T cells (5,12,36).The ability of VZV to replicate in noncycling cells is shared with herpes simplex viruses (HSV), which grow in similar cell types. HSV has acquired several viral genes that are critical for in vivo infection whose importance is cell type specific. These include ...

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Section: Discussionmentioning

confidence: 99%

Roscovitine, a Cyclin-Dependent Kinase Inhibitor, Prevents Replication of Varicella-Zoster Virus

Taylor

Kinchington

Cuba

et al. 2004

J Virol

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“…The striking lack of response to IV acyclovir, manifested by an elevated viral load after 2 weeks of treatment, is consistent with reports of acyclovir-resistant VZV infection after chronic oral acyclovir use. 18,19 His paraparesis with sensory and autonomic dysfunction was suspicious for progressive VZV myelitis with underlying HIV myelopathy. In immunocompetent individuals, postinfectious myelitis resolves spontaneously with or without steroid therapy, while the same can be fatal among the immunocompromised due to spinal cord invasion.…”

Section: Discussionmentioning

confidence: 99%

Complications of Varicella Zoster Infection of the Central Nervous System

Thomas

Perez

2017

Methodist DeBakey Cardiovascular Journal

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“…In HIV patients it may present in diverse manner such as multidermatomal involvement, crusted, nodular, vesiculopustular, ulcerative or ecthymatous [5][6][7] lesions that may be widely disseminated [5,[8][9][10] or localized [10].…”

Section: Introductionmentioning

confidence: 99%