Heterogeneous response for a mammalian hepadnavirus infection to acyclovir: Drug-arrested intermediates of minus-strand viral DNA synthesis are enveloped and secreted from infected cells as virion-like particles
✍ Scribed by Tencza, Michael G.; Newbold, John E.
- Publisher
- John Wiley and Sons
- Year
- 1997
- Tongue
- English
- Weight
- 584 KB
- Volume
- 51
- Category
- Article
- ISSN
- 0146-6615
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✦ Synopsis
Three woodchucks infected persistently with the woodchuck hepatitis virus (WHV) were treated with acyclovir (ACV) to investigate the effect of INTRODUCTION inhibiting viral DNA synthesis upon the replica-Dissection of the multiple steps involved in the replition of an orthohepadnavirus in vivo. Normal vication cycles of viruses is often achieved by genetic analraemia was reduced during the treatment period ysis. Mutant genomes have been exploited successfully in all three animals, but each responded with a for this purpose in hepadnaviruses [Chang et al., 1987; distinct serum phenotype. In the most provoca-Schlicht et al., 1987;Yaginuma et al., 1987], but the tive case, the profile of the WHV DNAs in both approach remains complicated by the overlapping nathe liver and serum provided a simple and novel ture of their genes and the parsimonious use of the viral description of the orthohepadnaviral infection for DNA that so characterizes the members of this virus this ACV protocol. The pre-drug viraemia was family [for a review, see Ganem and Varmus, 1987]. An rapidly cleared from the serum and replaced by additional strategy is to perturb the replication provirion-like particles containing predominantly cesses biochemically, usually with metabolic inhibitors, minus-strand WHV DNAs. These serum DNA speand obtain insight from the character of the modified, cies had the character of replicative intermediand perhaps abortive, infection. In the absence of suitates arrested in their elongation by ACV-mediable viral mutants, we have used the chemical approach ated chain termination and were contained in to specifically interrupt viral DNA synthesis for an orparticles with a buoyant density in CsCl essenthohepadnavirus in vivo. Several limited trials were tially identical with virions. However, in infected conducted with the woodchuck hepatitis virus (WHV) hepatocytes, initiation of reverse transcription system to permit preliminary evaluations of candidate within newly formed core particles was not inhibinhibitors, including the one described in this report, ited by the ACV treatment. Instead, an heterogeacyclovir (ACV).
ACV is an analogue of deoxyguanosine and is a well-neous array of minus-strand DNAs were synthecharacterised and specific inhibitor of DNA synthesis sised, each presumed to be truncated by the for members of the herpes virus family [Elion, 1993]. incorporation of one molecule of ACV mono-When tested in the duck hepatitis B virus (DHBV) sysphosphate. An approximately normal level of tem, administration of ACV to infected ducks produced core particles was present in the liver of this an immediate and stable reduction of viraemia, whether woodchuck after 26 days of the ACV protocol;
administered orally [Tsiquaye et al., 1986] or by intraexcess drug-arrested nucleocapsids were steadperitoneal injection (Cullen, J.M., Tencza, M.G., and ily removed throughout the dosing period upon Newbold, J.E., unpublished data). Now recognized as their envelopment and secretion as virion-like particles into the circulation. These data suggest that plus-strand DNA synthesis may not be absolutely required prior to secretion of virus from