Barrera Azeneth, Guerra Bernadette, Notvall Lena, Lanford Robert E
Department of Virology and Immunology, Southwest National Primate Research Center, Southwest Foundation for Biomedical Research, TX 78227, USA.
J Virol. 2005 Aug;79(15):9786-98. doi: 10.1128/JVI.79.15.9786-9798.2005.
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.
乙型肝炎病毒（HBV）和绒毛猴乙型肝炎病毒（WMHBV）是灵长类嗜肝DNA病毒，具有受限的组织和宿主嗜性。用HBV和WMHBV包膜假型化的丁型肝炎病毒（HDV）颗粒（HBV-HDV和WM-HDV）分别优先感染人肝细胞和蜘蛛猴肝细胞，从而在体外证实了宿主范围偏向性。对嵌合HBV和WMHBV大（L）包膜蛋白的分析表明，前S1结构域可能包含两个影响感染性的区域：一个在前S1的氨基末端40个氨基酸内，另一个在该区域的下游。在本研究中，我们通过检测合成肽竞争性阻断原代人肝细胞和蜘蛛猴肝细胞HDV感染的能力，进一步表征了前S1氨基末端在感染性中的作用。代表HBV L蛋白前S1结构域前45个残基的合成肽阻断了HBV-HDV和WM-HDV的感染性，氨基末端残基需要肉豆蔻酰化。用截短肽进行的竞争研究表明，前S1残基5至20代表抑制HDV感染的最小结构域，因此可能代表参与病毒-宿主受体相互作用的残基。在昆虫细胞中表达的重组前S1蛋白以1纳摩尔的浓度阻断了HBV-HDV和WM-HDV的感染。短前S1肽有效抑制HDV感染的能力表明它们是鉴定HBV受体的合适配体，并且前S1模拟物可能是治疗HBV感染的合理疗法。
