Mapping of the hepatitis B virus pre-S1 domain involved in receptor recognition.
Hepatitis B virus (HBV) and woolly monkey hepatitis B virus (WMHBV) are primate hepadnaviruses that display restricted tissue and host tropisms. Hepatitis D virus (HDV) particles pseudotyped with HBV and WMHBV envelopes (HBV-HDV and WM-HDV) preferentially infect human and spider monkey hepatocytes, respectively, thereby confirming host range bias in vitro. The analysis of chimeric HBV and WMHBV large (L) envelope proteins suggests that the pre-S1 domain may comprise two regions that affect infectivity: one within the amino-terminal 40 amino acids of pre-S1 and one downstream of this region. In the present study, we further characterized the role of the amino terminus of pre-S1 in infectivity by examining the ability of synthetic peptides to competitively block HDV infection of primary human and spider monkey hepatocytes. A synthetic peptide representing the first 45 residues of the pre-S1 domain of the HBV L protein blocked infectivity of HBV-HDV and WM-HDV, with a requirement for myristylation of the amino terminal residue. Competition studies with truncated peptides suggested that pre-S1 residues 5 to 20 represent the minimal domain for inhibition of HDV infection and, thus, presumably represent the residues involved in virus-host receptor interaction. Recombinant pre-S1 proteins expressed in insect cells blocked infection with HBV-HDV and WM-HDV at a concentration of 1 nanomolar. The ability of short pre-S1 peptides to efficiently inhibit HDV infection suggests that they represent suitable ligands for identification of the HBV receptor and that a pre-S1 mimetic may represent a rational therapy for the treatment of HBV infection.
Barrera
Azeneth
A
Department of Virology and Immunology, Southwest National Primate Research Center, Southwest Foundation for Biomedical Research, TX 78227, USA.
Guerra
Bernadette
B
Notvall
Lena
L
Lanford
Robert E
RE
D000595:Amino Acid Sequence; D000818:Animals; D002427:Cebidae; D002478:Cells, Cultured; D015613:Hepadnaviridae / Q000235:genetics / Q000502:physiology; D006515:Hepatitis B virus / Q000235:genetics / Q000502:physiology*; D003698:Hepatitis Delta Virus / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D023302:Protein Footprinting; D017434:Protein Structure, Tertiary / Q000235:genetics; D011991:Receptors, Virus / Q000032:analysis* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D013045:Species Specificity; D014759:Viral Envelope Proteins / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication
C096362:L protein, hepatitis B virus; D011991:Receptors, Virus; D011994:Recombinant Proteins; D014759:Viral Envelope Proteins