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Journal of Virology, July 2009, p. 6457-6463, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.00008-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Intracellular Localization of Hepatitis Delta Virus Proteins in the Presence and Absence of Viral RNA Accumulation{triangledown}

Ziying Han, Carolina Alves, Severin Gudima, and John Taylor*

Fox Chase Cancer Center, Philadelphia, Pennsylvania

Received 3 January 2009/ Accepted 11 April 2009

Hepatitis delta virus (HDV) encodes one protein, hepatitis delta antigen ({delta}Ag), a 195-amino-acid RNA binding protein essential for the accumulation of HDV RNA-directed RNA transcripts. It has been accepted that {delta}Ag localizes predominantly to the nucleolus in the absence of HDV genome replication while in the presence of replication, {delta}Ag facilitates HDV RNA transport to the nucleoplasm and helps redirect host RNA polymerase II (Pol II) to achieve transcription and accumulation of processed HDV RNA species. This study used immunostaining and confocal microscopy to evaluate factors controlling the localization of {delta}Ag in the presence and absence of replicating and nonreplicating HDV RNAs. When {delta}Ag was expressed in the absence of full-length HDV RNAs, it colocalized with nucleolin, a predominant nucleolar protein. With time, or more quickly after induced cell stress, there was a redistribution of both {delta}Ag and nucleolin to the nucleoplasm. Following expression of nonreplicating HDV RNAs, {delta}Ag moved to the nucleoplasm, but nucleolin was unchanged. When {delta}Ag was expressed along with replicating HDV RNA, it was found predominantly in the nucleoplasm along with Pol II. This localization was insensitive to inhibitors of HDV replication, suggesting that the majority of {delta}Ag in the nucleoplasm reflects ribonucleoprotein accumulation rather than ongoing transcription. An additional approach was to reevaluate several forms of {delta}Ag altered at specific locations considered to be essential for protein function. These studies provide evidence that {delta}Ag does not interact directly with either Pol II or nucleolin and that forms of {delta}Ag which support replication are also capable of prior nucleolar transit.

* Corresponding author. Mailing address: Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497. Phone: (215) 728 2436. Fax: (215) 728 3105. E-mail: john.taylor{at}fccc.edu

{triangledown} Published ahead of print on 15 April 2009.

Journal of Virology, July 2009, p. 6457-6463, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.00008-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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