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Journal of Virology, November 2009, p. 11152-11165, Vol. 83, No. 21
0022-538X/09/$08.00+0     doi:10.1128/JVI.00905-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Drastic Reduction in the Production of Subviral Particles Does Not Impair Hepatitis B Virus Virion Secretion{triangledown} ,{dagger}

Tamako Garcia,1 Jisu Li,2 Camille Sureau,3 Kiyoaki Ito,2 Yanli Qin,2 Jack Wands,2 and Shuping Tong2*

Graduate Program in Pathobiology, Division of Biology and Medicine, Brown University, Providence, Rhode Island,1 Liver Research Center, Rhode Island Hospital, Warren Alpert School of Medicine, Brown University, Providence, Rhode Island,2 Laboratoire de Virologie Moleculaire, INTS, Paris, France3

Received 6 May 2009/ Accepted 31 July 2009

Hepatitis B virus (HBV) contains three coterminal envelope proteins on the virion surface: large (L), middle (M), and small (S). The M and S proteins are also secreted as empty "subviral particles," which exceed virions by at least 1,000-fold. The S protein serves as the morphogenic factor for both types of particles, while the L protein is required only for virion formation. We found that cotransfecting replication constructs with a small dose of the expression construct for the missing L, M, and S proteins reconstituted efficient virion secretion but only 5 to 10% of subviral particles. The L protein inhibited secretion of subviral particles in a dose-dependent manner, whereas a too-high or too-low L/S protein ratio inhibited virion secretion. Consistent with the results of cotransfection experiments, a point mutation at the –3 position of the S gene AUG codon reduced HBsAg secretion by 60 to 70% but maintained efficient virion secretion. Surprisingly, ablating M protein expression reduced virion secretion but markedly increased the maturity of virion-associated genomes, which could be reversed by providing in trans both L and M proteins but not just M protein. M protein stability was dependent on the coexpression of S protein. Our findings suggest that efficient HBV virion secretion could be maintained despite drastic reduction in subviral particle production, which supports the recent demonstration of separate secretion pathways adopted by the two types of particles. The M protein appears to facilitate core particle envelopment, thus shortening the window of plus strand DNA elongation.

* Corresponding author. Mailing address: Liver Research Center, 55 Claverick St., 4th Floor, Providence, RI 02903. Phone: (401) 444-7365. Fax: (401) 444-2939. E-mail: shuping_tong_md{at}brown.edu

{triangledown} Published ahead of print on 12 August 2009.

{dagger} This paper is dedicated to the memory of T. S. Benedict Yen for his contribution to HBV research.

Journal of Virology, November 2009, p. 11152-11165, Vol. 83, No. 21
0022-538X/09/$08.00+0     doi:10.1128/JVI.00905-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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