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Journal of Virology, September 2007, p. 9050-9060, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.00479-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Hepatitis B Virus Maturation Is Sensitive to Functional Inhibition of ESCRT-III, Vps4, and {gamma}2-Adaptin{triangledown}

Carsten Lambert, Tatjana Döring, and Reinhild Prange*

Department of Medical Microbiology and Hygiene, Johannes Gutenberg-Universität Mainz, D-55101 Mainz, Germany

Received 7 March 2007/ Accepted 1 June 2007

Hepatitis B virus (HBV) is an enveloped DNA virus that presumably buds at intracellular membranes of infected cells. HBV budding involves two endocytic host proteins, the ubiquitin-interacting adaptor {gamma}2-adaptin and the Nedd4 ubiquitin ligase. Here, we demonstrate that HBV release also requires the cellular machinery that generates internal vesicles of multivesicular bodies (MVBs). In order to perturb the MVB machinery in HBV-replicating liver cells, we used ectopic expression of dominant-negative mutants of different MVB components, like the ESCRT-III complex-forming CHMP proteins and the Vps4 ATPases. Upon coexpression of mutated CHMP3, CHMP4B, or CHMP4C forms, as well as of ATPase-defective Vps4A or Vps4B mutants, HBV assembly and egress were potently blocked. Each of the MVB inhibitors arrested virus particle maturation by entrapping the viral core and large and small envelope proteins in detergent-insoluble membrane structures that closely resembled aberrant endosomal class E compartments. In contrast, HBV subvirus particle release was not affected by MVB inhibitors, hinting at different export routes used by viral and subviral particles. To further define the role {gamma}2-adaptin plays in HBV formation, we examined the effects of its overexpression in virus-replicating cells. Intriguingly, excess {gamma}2-adaptin blocked HBV production in a manner similar to the actions of CHMP and Vps4 mutants. Moreover, overexpressed {gamma}2-adaptin perturbed the endosomal morphology and diminished the budding of a retroviral Gag protein, implying that it may act as a principal inhibitor of the MVB sorting pathway. Together, these results demonstrate that HBV exploits the MVB machinery with the aid of {gamma}2-adaptin.

* Corresponding author. Mailing address: Department of Medical Microbiology and Hygiene, University of Mainz, Augustusplatz, D-55101 Mainz, Germany. Phone: 49-6131-3936750. Fax: 49-6131-3932359. E-mail: prange{at}mail.uni-mainz.de

{triangledown} Published ahead of print on 6 June 2007.

Journal of Virology, September 2007, p. 9050-9060, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.00479-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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