Envelope protein-mediated down-regulation of hepatitis B virus receptor ininfected hepatocytes

Entry of duck hepatitis B virus (DHBV) is initiated by specific interaction of its large envelope protein (L) with a cellular entry receptor, recently identified as carboxypeptidase D (CPD; historically gp180). In this report , we present evidence demonstrating that this receptor is down-regulated as a result of DHBV infection: (i) receptor levels determined by Western blot were much reduced in DHBV-infected duck livers and undetectable by immunos taining in infected cultured hepatocytes; (ii) results from metabolic label ing experiments indicate enhanced receptor protein turnover; (iii) the kine tics of receptor loss from newly infected cells correlated with the accumul ation of newly synthesized viral protein; (iv) expression of DHBV L protein , transduced from a recombinant adenovirus, was sufficient to eliminate gp1 80/CPD from the Golgi compartment, its normal predominant location; (v) gp1 80/CPD remained absent from the Golgi compartment in infected hepatocytes, even after overexpression from a recombinant adenovirus, while residual amo unts subsequently became detectable in a perinuclear compartment, containin g DHBV L protein; (vi) expression of DHBV L protein in a HepG2 cell line, s tably expressing gp180/CPD, leads to incomplete receptor maturation and ind uces its degradation. Taken together, these data are consistent with a mode l in which the virus receptor interacts early in the biosynthetic pathway w ith the viral L protein, leading to its retention in a pre-Golgi compartmen t and to subsequent degradation, thus preventing receptor interference with the export of DHBV via the secretory pathway which it shares with its rece ptor. Accordingly, and analogously with receptor down-regulation in retrovi ral systems, DHBV receptor down-modulation may account for the much-reduced efficiency of DHBV superinfection of preinfected hepatocytes.