Analysis of Host Range Phenotypes of Primate Hepadnaviruses by In Vitro Infections of Hepatitis D Virus Pseudotypes

ABSTRACT Hepatitis B virus (HBV) and woolly monkey hepatitis B virus (WMHBV) have natural host ranges that are limited to closely related species. The barrier for infection of primates seems to be at the adsorption and/or entry steps of the viral replication cycle, since a human hepatoma cell line is permissive for HBV and WMHBV replication following transfection of cloned DNA. We hypothesized that the HBV and WMHBV envelope proteins contain the principal viral determinants of host range. As previously shown by using the hepatitis D virus (HDV) system, recombinant HBV-HDV particles were infectious in chimpanzee as well as human hepatocytes. We extended the HDV system to include HDV particles pseudotyped with the WMHBV envelope. In agreement with the natural host ranges of HBV and WMHBV, in vitro infections demonstrated that HBV-HDV and WM-HDV particles preferentially infected human and spider monkey cells, respectively. Previous studies have implicated the pre-S1 region of the large (L) envelope protein in receptor binding and host range; therefore, recombinant HDV particles were pseudotyped with the hepadnaviral envelopes containing chimeric L proteins with the first 40 amino acids from the pre-S1 domain exchanged between HBV and WMHBV. Surprisingly, addition of the human amino terminus to the WMHBV L protein increased infectivity on spider monkey hepatocytes but did not increase infectivity for human hepatocytes. Based upon these data, we discuss the possibility that the L protein may be comprised of two domains that affect infectivity and that sequences downstream of residue 40 may influence host range and receptor binding or entry.

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Mapping of the Hepatitis B Virus Pre-S1 Domain Involved in Receptor Recognition

Journal of Virology ◽

10.1128/jvi.79.15.9786-9798.2005 ◽

2005 ◽

Vol 79 (15) ◽

pp. 9786-9798 ◽

Cited By ~ 85

Author(s):

Azeneth Barrera ◽

Bernadette Guerra ◽

Lena Notvall ◽

Robert E. Lanford

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Spider Monkey ◽

Receptor Interaction ◽

Hepatitis D ◽

Woolly Monkey ◽

Amino Terminal ◽

B Virus ◽

Hdv Infection

ABSTRACT 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.

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Hepatitis D Virus Infection Among Hepatitis B Virus Surface Antigen Positive Individuals

Case Medical Research ◽

10.31525/ct1-nct04038372 ◽

2019 ◽

Author(s):

Keyword(s):

Hepatitis B Virus ◽

Virus Infection ◽

Hepatitis B ◽

Surface Antigen ◽

Hepatitis D ◽

Virus Surface ◽

Virus Surface Antigen ◽

Hepatitis D Virus ◽

B Virus

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Epitope–Paratope Interaction of a Neutralizing Human Anti-Hepatitis B Virus PreS1 Antibody That Recognizes the Receptor-Binding Motif

Vaccines ◽

10.3390/vaccines9070754 ◽

2021 ◽

Vol 9 (7) ◽

pp. 754

Author(s):

Jisu Hong ◽

Youngjin Choi ◽

Yoonjoo Choi ◽

Jiwoo Lee ◽

Hyo Jeong Hong

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Receptor Binding ◽

Neutralizing Antibody ◽

Hbv Infection ◽

Binding Motif ◽

Alanine Scanning Mutagenesis ◽

B Virus ◽

Complementarity Determining Regions

Hepatitis B virus (HBV) is a global health burden that causes acute and chronic hepatitis. To develop an HBV-neutralizing antibody that effectively prevents HBV infection, we previously generated a human anti-preS1 monoclonal antibody (1A8) that binds to genotypes A–D and validated its HBV-neutralizing activity in vitro. In the present study, we aimed to determine the fine epitope and paratope of 1A8 to understand the mechanism of HBV neutralization. We performed alanine-scanning mutagenesis on the preS1 (aa 19–34, genotype C) and the heavy (HCDR) and light (LCDR) chain complementarity-determining regions. The 1A8 recognized the three residues (Leu22, Gly23, and Phe25) within the highly conserved receptor-binding motif (NPLGFFP) of the preS1, while four CDR residues of 1A8 were critical in antigen binding. Structural analysis of the epitope–paratope interaction by molecular modeling revealed that Leu100 in the HCDR3, Ala50 in the HCDR2, and Tyr96 in the LCDR3 closely interacted with Leu22, Gly23, and Phe25 of the preS1. Additionally, we found that 1A8 also binds to the receptor-binding motif (NPLGFLP) of infrequently occurring HBV. The results suggest that 1A8 may broadly and effectively block HBV entry and thus have potential as a promising candidate for the prevention and treatment of HBV infection.

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Chronic Hepatitis D Virus (HDV) Infection in Hepatitis B Virus Carrier Chimpanzees Experimentally Superinfected with HDV

The Journal of Infectious Diseases ◽

10.1093/infdis/158.1.151 ◽

1988 ◽

Vol 158 (1) ◽

pp. 151-159 ◽

Cited By ~ 32

Author(s):

F. Negro ◽

K. F. Bergmann ◽

B. M. Baroudy ◽

W. C. Satterfield ◽

H. Popper ◽

...

Keyword(s):

Chronic Hepatitis ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Hepatitis D ◽

Hepatitis D Virus ◽

B Virus ◽

Hepatitis B Virus Carrier ◽

Hdv Infection ◽

Virus Carrier

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Origins and Evolution of Hepatitis B Virus and Hepatitis D Virus

Cold Spring Harbor Perspectives in Medicine ◽

10.1101/cshperspect.a021360 ◽

2016 ◽

Vol 6 (1) ◽

pp. a021360 ◽

Cited By ~ 51

Author(s):

Margaret Littlejohn ◽

Stephen Locarnini ◽

Lilly Yuen

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Hepatitis D ◽

Hepatitis D Virus ◽

B Virus

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Study of the Impact of Hepatitis D Virus Infection on Chronic Hepatitis B Virus Patients in Egypt

International Journal of Current Microbiology and Applied Sciences ◽

10.20546/ijcmas.2016.502.050 ◽

2016 ◽

Vol 5 (2) ◽

pp. 449-458 ◽

Cited By ~ 2

Author(s):

Mohamed Abdel-Hamid Ahmed ◽

MostafaSaleh Abdel-Motaleb Sheemy ◽

Nagwa Sedky ◽

Gamal Esmat ◽

Azza Abdul-Azim Gomaa

Keyword(s):

Chronic Hepatitis ◽

Hepatitis B Virus ◽

Virus Infection ◽

Hepatitis B ◽

Chronic Hepatitis B ◽

Hepatitis D ◽

Hepatitis D Virus ◽

Chronic Hepatitis B Virus ◽

B Virus ◽

The Impact

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Prevalence of hepatitis D virus infection among hepatitis B virus-infected individuals in India

Indian Journal of Gastroenterology ◽

10.1007/s12664-015-0555-6 ◽

2015 ◽

Vol 34 (2) ◽

pp. 164-168 ◽

Cited By ~ 4

Author(s):

Shankar Lal Jat ◽

Neha Gupta ◽

Tarun Kumar ◽

Swapnil Mishra ◽

Avani S ◽

...

Keyword(s):

Hepatitis B Virus ◽

Virus Infection ◽

Hepatitis B ◽

Hepatitis D ◽

Hepatitis D Virus ◽

B Virus

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Implications of Efficient Hepatic Delivery by Tenofovir Alafenamide (GS-7340) for Hepatitis B Virus Therapy

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00128-15 ◽

2015 ◽

Vol 59 (6) ◽

pp. 3563-3569 ◽

Cited By ~ 72

Author(s):

Eisuke Murakami ◽

Ting Wang ◽

Yeojin Park ◽

Jia Hao ◽

Eve-Irene Lepist ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Human Hepatocytes ◽

Target Tissue ◽

Small Contribution ◽

Primary Human Hepatocytes ◽

B Virus ◽

Tenofovir Alafenamide ◽

Pharmacologically Active

ABSTRACTTenofovir alafenamide (TAF) is a prodrug of tenofovir (TFV) currently in clinical evaluation for treatment for HIV and hepatitis B virus (HBV) infections. Since the target tissue for HBV is the liver, the hepatic delivery and metabolism of TAF in primary human hepatocytesin vitroand in dogsin vivowere evaluated here. Incubation of primary human hepatocytes with TAF resulted in high levels of the pharmacologically active metabolite tenofovir diphosphate (TFV-DP), which persisted in the cell with a half-life of >24 h. In addition to passive permeability, studies of transfected cell lines suggest that the hepatic uptake of TAF is also facilitated by the organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3, respectively). In order to inhibit HBV reverse transcriptase, TAF must be converted to the pharmacologically active form, TFV-DP. While cathepsin A is known to be the major enzyme hydrolyzing TAF in cells targeted by HIV, including lymphocytes and macrophages, TAF was primarily hydrolyzed by carboxylesterase 1 (CES1) in primary human hepatocytes, with cathepsin A making a small contribution. Following oral administration of TAF to dogs for 7 days, TAF was rapidly absorbed. The appearance of the major metabolite TFV in plasma was accompanied by a rapid decline in circulating TAF. Consistent with thein vitrodata, high and persistent levels of TFV-DP were observed in dog livers. Notably, higher liver TFV-DP levels were observed after administration of TAF than those given TDF. These results support the clinical testing of once-daily low-dose TAF for the treatment of HBV infection.

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