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Journal of Virology, December 2009, p. 12443-12451, Vol. 83, No. 23
0022-538X/09/$08.00+0     doi:10.1128/JVI.01594-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Pre-S1 and Antigenic Loop Infectivity Determinants of the Hepatitis B Virus Envelope Proteins Are Functionally Independent{triangledown}

Yann Le Duff,1 Matthieu Blanchet,1 and Camille Sureau1,2*

Laboratoire de Virologie, INTS, Paris 75739, France,1 Department of Virology and Immunology, Southwest Foundation for Biomedical Research, San Antonio, Texas 782282

Received 31 July 2009/ Accepted 10 September 2009

The hepatitis B virus (HBV) envelope proteins bear two determinants of viral entry: a receptor-binding site (RBS) in the pre-S1 domain of the large envelope protein and a conformation-dependent determinant, of unknown function, in the antigenic loop (AGL) of the small, middle, and large envelope proteins. Using an in vitro infection assay consisting of susceptible HepaRG cells and the hepatitis delta virus (HDV) as a surrogate of HBV, we first investigated whether subelements of the pre-S1 determinant (amino acids 2 to 75), i.e., the N-terminal myristoyl anchor, subdomain 2-48 (RBS), and subdomain 49-75, were functionally separable. In transcomplementation experiments, coexpression of two distinct infectivity-deficient pre-S1 mutants at the surface of HDV virions failed to restore infectivity, indicating that the myristoyl anchor, the 2-48 RBS, and the 49-75 sequence, likely cooperate in cis at viral entry. Furthermore, we showed that as much as 52% of total pre-S1 in the HDV envelope could bear infectivity-deficient lesions without affecting entry, indicating that a small number of pre-S1 polypeptides—estimated at three to four per virion—is sufficient for infectivity. We next investigated the AGL activity in the small or large envelope protein background (S- and L-AGL, respectively) and found that lesions in S-AGL were more deleterious to infectivity than in L-AGL, a difference that reflects the relative stoichiometry of the small and large envelope proteins in the viral envelope. Finally, we showed that C147S, an AGL infectivity-deficient substitution, exerted a dominant-negative effect on infectivity, likely reflecting an involvement of C147 in intermolecular disulfide bonds.

* Corresponding author. Mailing address: Laboratoire de Virologie, Institut National de la Transfusion Sanguine, 6 Rue Alexandre Cabanel, Paris 75739, France. Phone: (33) 1-44-49-30-56. Fax: (33) 1-44-49-30-59. E-mail: csureau{at}ints.fr

{triangledown} Published ahead of print on 16 September 2009.

Journal of Virology, December 2009, p. 12443-12451, Vol. 83, No. 23
0022-538X/09/$08.00+0     doi:10.1128/JVI.01594-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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