Identification of the immunogenic domains in HBsAg preS1 region using overlapping preS1 fragment fusion proteins

Hu, Weiguo; Wei, Jun; Xia, Hengchuan; Yang, Xin-Xiu; Li, Feng; Li, Guangdi; Wang, Yuan; Zhang, Zu-Chuan

doi:10.3748/wjg.v11.i14.2088

Cited by 12 publications

(17 citation statements)

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“…optimization [Hu et al, 2005], both provide insight into the conformational and linear epitopes to which major antibody responses are directed during infection. Abundant immunogenic domains and B cell epitopes that exist within the preS1 region [Hu et al, 2005] may provide an alternate target to HBsAg.…”

Section: Immunological Detection Of Hbsag Mutantsmentioning

confidence: 99%

Detection of HBsAg mutants

Osiowy

2006

J. Med. Virol.

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HBsAg screening is carried out routinely to detect hepatitis B virus (HBV) infection. The immunoassays used employ capture antibodies often having specificity for epitopes present on the antigenic (a) determinant of the HBsAg. Loss of detection may occur due to mutations within and/or outside of the a determinant that affect conformational epitope recognition or HBsAg secretion or expression. Most of the mutations associated with immune escape occur within the second loop of the a determinant. In order to detect these HBsAg mutants, antibodies to subdominant regions within the a determinant or outside of the HBsAg may be required, and this has been the focus of many recent studies. Any changes to immunoassay formulations should also address the possible effect of HBV genotypic polymorphisms on assay specificity and sensitivity. HBsAg mutants may also be identified through nucleic acid detection of HBV in serum. Various molecular analysis methods have been developed to provide specific and sensitive detection of HBsAg mutants, including sequencing, limiting dilution cloning PCR (LDC-PCR), gap ligase chain reaction (gLCR), and real time PCR. Sequencing the HBsAg coding region provides specific information on the nucleotide sequence; however, it is relatively insensitive for the detection of minority quasispecies. Other nucleic acid methods offer greater sensitivity for the detection of point mutations. To improve immunoassays, further research will be required to increase detection sensitivity and specificity. Ultimately, a better understanding of the structure of antibody-bound HBsAg will help identify the immunological targets required for the accurate detection of HBsAg in blood.

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Section: Immunological Detection Of Hbsag Mutantsmentioning

confidence: 99%

Detection of HBsAg mutants

Osiowy

2006

J. Med. Virol.

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“…Although not all NMR parameters in unison point to the same location of pre-structured regions, we were able to reasonably map out the prestructured regions or motifs. Figure 6 summarizes the location of the pre-structured motifs delineated in this study, as well as the previously suggested immunodominant or hepatocyte-binding domains (Neurath et al 1992;Barrera et al 2005;Glebe et al 2005;Hu et al 2005;Engelke et al 2006). As summarized in Figure 6 there is a general correlation between presence of the pre-structured motifs and immunogenicity or hepatocyte-binding ability in preS1.…”

Section: Discussionmentioning

confidence: 93%

“…The gray bars are for residues showing an intermediate degree of structural ordering and the hatched bars for least prestructuring residues. Shown below the amino acid sequence of preS1 are the previously reported functionally important domains; the putative hepatocyte receptor-binding domain with a green (Neurath et al 1986) or a red bar (Barrera et al 2005), hepatocyte attachment domains with blue bars (Glebe et al 2005), and an immunogenic domain with a violet bar (Hu et al 2005), respectively.…”

Section: Protein Preparationmentioning

confidence: 99%

“…Another investigation, yet, revealed that the residues 16-31 are sufficient for hepatocyte binding (Barrera et al 2005). Furthermore, a recent antibody screening study argues that residues 34-59 should be involved with hepatocyte binding (Hu et al 2005).…”

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confidence: 99%

“…A prerequisite for such an attempt is to know which fragment to use (Barrera et al 2005;Glebe et al 2005;Hu et al 2005). One may simply use the putative heptatocyte-binding domain encompassing residues 21-47 (Neurath et al 1986).…”

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Pre‐structured motifs in the natively unstructured preS1 surface antigen of hepatitis B virus

et al. 2007

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The preS1 surface antigen of hepatitis B virus (HBV) is known to play an important role in the initial attachment of HBV to hepatocytes. We have characterized structural features of the full-length preS1 using heteronuclear NMR methods and discovered that this 119-residue protein is inherently unstructured without a unique tertiary structure under a nondenaturing condition. Yet, combination of various NMR parameters shows that the preS1 contains ''pre-structured'' domains broadly covering its functional domains. The most prominent domain is formed by residues 27-45 and overlaps with the putative hepatocyte-binding domain (HBD) encompassing residues 21-47, within which two welldefined pre-structured motifs, formed by Pro 32 -Ala 36 and Pro 41 -Phe 45 are found. Additional, somewhat less prominent, pre-structured motifs are also formed by residues 11-18, 22-25, 37-40, and 46-50. Overall results suggest that the preS1 is a natively unstructured protein (NUP) whose N-terminal 50 residues, populated with multiple pre-structured motifs, contribute critically to hepatocyte binding.Keywords: hepatitis B virus; preS1; NMR; natively unstructured protein; pre-structured motif Supplemental material: see www.proteinscience.org Hepatitis B virus (HBV) is a member of the hepadnaviridae family (Ganem and Varmus 1987;Chisari et al. 1989) that poses a significant health threat to millions of people worldwide, particularly in Africa, Asia, and certain parts of Europe (Fung and Lok 2004;Wright 2006). Whereas HBV infection itself may not appear so fatal as AIDS or SARS chronic hepatitis B infection often develops into more serious symptoms such as cirrhosis, liver failure, and hepatocelluar carcinoma (Blumberg et al. 1989). While successful administration of HBV vaccines led to a significant reduction of HBV-related casualties (Stephenne 1990;Mahoney et al. 1993;Jilg 1998;Poland and Jacobson 2004), emergence of escape mutants or nonresponders to current vaccines argues for attempts to develop vaccines with better efficacy. In addition, more specific anti-HBV therapeutics are needed in order to completely eradicate HBV infection, since nucleoside drugs currently in use for HBV-related symptoms are not HBV specific, often causing side effects or inducing drug resistance. Efforts to discover anit-HBVspecific agents based upon natural products or siRNAs have been met with only partial success (Saag 2006;Shin et al. 2006).Even though it is generally accepted that HBV infection begins with an attachment of HBV surface antigens to a HBV-specific hepatocyte receptor, followed by subsequent entry of viral DNA into hepatocyte (Neurath 3 These authors contributed equally to this work. Reprint requests to: Kyou-Hoon Han, Molecular Cancer Research Center, Division of Molecular Therapeutics, KRIBB, Daejeon 305-806, Korea; e-mail: khhan600@kribb.re.kr; fax: 82-42-860-4259.Abbreviations: HBV, hepatitis B virus; NMR, nuclear magnetic resonance; NUP, natively unstructured protein; CSI, chemical-shift index.Article published online ahead of pr...

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Vaccines targeting preS1 domain overcome immune tolerance in hepatitis B virus carrier mice

et al. 2017

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Strong tolerance to HBV surface antigens limits the therapeutic effect of the conventional HBsAg vaccination in both preclinical animal models and patients with chronic hepatitis B (CHB) infection. In contrast, we observed that clinical CHB patients presented less immune tolerance to the preS1 domain of HBV large surface antigen. To study whether targeting the weak tolerance of preS1 region could improve therapy gain, we explored vaccination with the long peptide of preS1 domain for HBV virions clearance. Our study showed that this preS1-polypeptide rather than HBsAg vaccination induced robust immune responses in the HBV carrier mice. The anti-preS1 rapidly cleared HBV virions in vivo and blocked HBV infection to hepatocytes in vitro. Intriguingly, vaccination of preS1-polypeptide even reduced the tolerized status of HBsAg, opening a therapeutic window for the host to respond to the HBsAg vaccine. A sequential administration of antigenically distinct preS1-polypeptide and HBsAg vaccines in HBV carrier mice could finally induce HBsAg-HBsAb serological conversion and clear chronic HBV infection in the carrier mice. These results suggest that preS1 can function as a therapeutic vaccination for the control of CHB.

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Identification of the immunogenic domains in HBsAg preS1 region using overlapping preS1 fragment fusion proteins

Cited by 12 publications

References 41 publications

Detection of HBsAg mutants

Detection of HBsAg mutants

Pre‐structured motifs in the natively unstructured preS1 surface antigen of hepatitis B virus

Vaccines targeting preS1 domain overcome immune tolerance in hepatitis B virus carrier mice

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