g., entry.2 HBV is a member of the hepadnaviridae.3 Hepadnaviruses are the smallest enveloped DNA viruses that replicate buy BTK inhibitor by way of reverse transcription of a pregenomic RNA (pgRNA) intermediate.
During assembly the nucleocapsid acquires three viral envelope proteins termed large (L), middle (M), and small (S). They are encoded in one open reading frame and share the S-domain, which is required for membrane anchoring. In addition to the S-domain, M contains an N-terminal hydrophilic extension of 55 amino acids (preS2), while L is further extended by 107, 117, or 118 amino acids (genotype-dependent), termed preS1.4 The myristoylated preS1-domain of L plays the key role in HBV and hepatitis delta virus (HDV) infectivity through mediating attachment and specific receptor binding.5-13 Hepadnaviruses show pronounced species specificities. In addition to humans, only chimpanzees are susceptible to HBV.14 The fact that mice and rats are refractory to HBV has been attributed to the lack of either entry factor(s) or the presence of postentry restriction factors. Since delivery of plasmid-encoded HBV-genomes into hepatic
cells of nonsusceptible species promote virion secretion, it is assumed that host constraints are related to early infection events.15 Another peculiarity of HBV is the efficacy to selectively infect hepatocytes in vivo, a feature that becomes particularly
click here apparent when the virus is administered at very low inoculation doses. Injection of <10 virions establishes an infection in chimpanzees.16 The hypothesis that the species specificity and the extraordinary liver tropism are associated with an early step of HBV infection, e.g., specific receptor recognition, is attractive. However, experimental proof for this was hampered until cell culture systems for HBV and HDV, a virusoid using the HBV envelope to propagate, became available.17, 18 Using subviral particles and primary Tupaia hepatocytes (PTH), Glebe et al.13 showed that specific binding depends on the L-protein. We identified HBV L-protein-derived lipopeptides that block HBV and HDV 上海皓元 infection of primary human hepatocytes (PHH) and HepaRG cells.7, 19, 20 The peptides are active when subcutaneously injected into PHH-transplanted urokinase plasminogen activator, severe combined immunodeficient (uPA-SCID) mice, a small, immune-deficient animal model used to study HBV infection in vivo.21 They represent the N-terminal 47 amino acids of the preS1-domain of HBV (HBVpreS/2-48myr) and include the naturally occurring modification with myristic acid. Since preincubation of cells with HBVpreS/2-48myr blocks infection they presumably address a receptor. Direct evidence, therefore, comes from in vitro binding studies using fluorescently labeled HBVpreS-derived lipopeptides (Meier et al.22).