Dataset Information

Structural and Epitope Analysis (T- and B-Cell Epitopes) of Hepatitis C Virus (HCV) Glycoproteins: An in silico Approach.

ABSTRACT: Background:Chronic infection with Hepatitis C Virus (HCV) poses a major risk for liver disease like cirrhosis, liver failure and hepatocellular carcinoma. In terms of percentage, the prevalence of HCV in India was found to be low to moderate (1-1.5%), but in terms of sheer numbers, India has a significant number of global HCV patients. Presently, HCV can be treated with direct acting-antibody drugs but there is no prophylactic or therapeutic vaccine available against it. In HCV infection, T- and B-cell immunity is important for clearing the virus. In the present study immunoinformatics was used to identify potent vaccine target for HCV vaccine development. Methods:Sequence of HCV was retrieved from NCBI and their structural analysis was done by using Protpram, PSIPRED, iTASSER and PDBsum servers. T-cell and B-cell epitopes were predicted by Immune Epitope Database and ACBPRED servers. Results:On epitope prediction, 25 and 55 potent MHC-I epitopes and 7 and 13 potent B-cell epitopes were predicted for E1 and E2 protein respectively. Their antigenicity score was also calculated. The most potent MHC-I epitopes were MMMNWSPAV and MAWDMMMNW for HLA-A*02:01 and HLA-B*53:01 and most potent B-cell epitope was TGHRMAWDMMMNWSPA for E1 protein. For E2, four MHC-I epitopes having the lowest binding energy and most potent B-cell epitope was DRPYCWHYAPRPCDTI. Conclusion:In the present study, most potent epitopes for HCV was determined on the basis of their antigenicity along with 3D modeling and docking. Identified B- and T-cell epitopes can be used for the development of potent vaccine against most prevalent HCV type in India to limit its infection.

SUBMITTER: Kumar A

PROVIDER: S-EPMC6286880 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Structural and Epitope Analysis (T- and B-Cell Epitopes) of Hepatitis C Virus (HCV) Glycoproteins: An <i>in silico</i> Approach.

Kumar Anoop A Pandey Roma R Yadav Inderjit S IS Bharadwaj Mausumi M

Journal of clinical and experimental hepatology 20180221 4

<h4>Background</h4>Chronic infection with Hepatitis C Virus (HCV) poses a major risk for liver disease like cirrhosis, liver failure and hepatocellular carcinoma. In terms of percentage, the prevalence of HCV in India was found to be low to moderate (1-1.5%), but in terms of sheer numbers, India has a significant number of global HCV patients. Presently, HCV can be treated with direct acting-antibody drugs but there is no prophylactic or therapeutic vaccine available against it. In HCV infection ...[more]

PMID: 30568344

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Project description:The genome of hepatitis C virus (HCV) consists of seven functional regions: the core, E1, E2/NS1, NS2, NS3, NS4, and NS5 regions. The U. S. Food and Drug Administration-licensed 2.0G immunoassay for the detection of anti-HCV uses proteins from the core, NS3, and NS4 regions (McHutchinson et al., Hepatology 15:19-25, 1992). The 3.0G enzyme-linked immunosorbent assay includes the protein from the NS5 region (Uyttendaele et al., Vox Sang. 66:122-129, 1994). The necessity of detecting antibodies to viral envelope proteins (E1 and E2) and to different genotype samples has been demonstrated previously (Chien et al., Lancet 342:933, 1993; Lok et al., Hepatology 18:497-502, 1993). In this study we have attempted to improve the sensitivity of the anti-HCV assay by developing a single multiple-epitope fusion antigen (MEFA; MEFA-6) which incorporates all of the major immunodominant epitopes from the seven functional regions of the HCV genome. A nucleic acid sequence consisting of proteins from the viral core, E1, E2, NS3, NS4, and NS5 regions and different subtype-specific regions of the NS4 region was constructed, cloned, and expressed in yeast. The epitopes present on this antigen can be detected by epitope-specific monoclonal and polyclonal antibodies. In a competition assay, the MEFA-6 protein competed with 83 to 96% of genotype-specific antibodies from HCV genotype-specific peptides. This recombinant antigen was subsequently used to design an anti-HCV chemiluminescent immunoassay. We designed our assay using a monoclonal anti-human immunoglobulin G antibody bound to the solid phase. Because MEFA-6 is fused with human superoxide dismutase (h-SOD), we used an anti-human superoxide dismutase, dimethyl acridinium ester-labeled monoclonal antibody for detection. Our results indicate that MEFA-6 exposes all of the major immunogenic epitopes. Its excellent sensitivity and specificity for the detection of clinical seroconversion are demonstrated by this assay.

Project description:The hepatitis C virus (HCV) E2 glycoprotein is a major target of the neutralizing antibody (nAb) response, with multiple type-specific and broadly neutralizing antibody (bnAb) epitopes identified. The 412-to-423 region can generate bnAbs that block interaction with the cell surface receptor CD81, with activity toward multiple HCV genotypes. In this study, we reveal the structure of rodent monoclonal antibody 24 (MAb24) with an extensive contact area toward a peptide spanning the 412-to-423 region. The crystal structure of the MAb24-peptide 412-to-423 complex reveals the paratope bound to a peptide hairpin highly similar to that observed with human MAb HCV1 and rodent MAb AP33, but with a different angle of approach. In viral outgrowth experiments, we demonstrated three distinct genotype 2a viral populations that acquired resistance to MAb24 via N415D, N417S, and N415D/H386R mutations. Importantly, the MAb24-resistant viruses exhibited significant increases in sensitivity to the majority of bnAbs directed to epitopes within the 412-to-423 region and in additional antigenic determinants located within E2 and the E1E2 complex. This study suggests that modification of N415 causes a global change in glycoprotein structure that increases its vulnerability to neutralization by other antibodies. This finding suggests that in the context of an antibody response to viral infection, acquisition of escape mutations in the 412-to-423 region renders the virus more susceptible to neutralization by other specificities of nAbs, effectively reducing the immunological fitness of the virus. A vaccine for HCV that generates polyspecific humoral immunity with specificity for the 412-to-423 region and at least one other region of E2 is desirable.IMPORTANCE Understanding how antibodies neutralize hepatitis C virus (HCV) is essential for vaccine development. This study reveals for the first time that when HCV develops resistance to a major class of bnAbs targeting the 412-to-423 region of E2, this results in a concomitant increase in sensitivity to neutralization by a majority of other bnAb specificities. Vaccines for the prevention of HCV infection should therefore generate bnAbs directed toward the 412-to-423 region of E2 and additional bnAb epitopes within the viral glycoproteins.

Project description:The bovine leukaemia virus (BLV) is a retrovirus responsible for enzootic bovine leukaemia (EBL) disease, the most common cattle disease leading to high annual economic losses to the cattle breeding industry. Virus monitoring among the sheep and cattle herds is usually done by vaccination. Inactivated virus vaccines can partially protect the livestock from viral challenge. However, vaccinated animals are likely to be infected. So, there is an essential need for producing vaccine by other methods. Gp60 SU, encoded by Env gene, is the surface glycoprotein of BLV detected to be the major target for the host immunity against the virus. Different stages were performed to predict the potential B and T-helper cell epitopes. The general framework of the method includes retrieving the amino acid sequence of gp60 SU, conducting the sequence alignment, getting the entropy plot, retrieving the previously found epitopes, predicting the hydropathy parameters, modelling the tertiary structure of the glycoprotein, minimizing the structure energy, validating the model by Ramachandran plot, predicting the linear and discontinuous epitopes by various servers and eventually choosing the consensus immunogenic regions. Ramachandran plot scrutiny has demonstrated that the modelled prediction is accurate and suitable. By surveying overlaps of various results, 4 and 2 immunogenic regions were selected as linear and conformational epitopes respectively. Amino acids 35-53, 67-97, 288-302 and 410-421 and those of numbers 37-58 and 72-100 were the regions selected as linear and conformational epitopes respectively. The tertiary structure of the final epitope was modelled as well. A comparison of the predicted epitopes structure with that of gp60 SU envelope, illustrated that the tertiary structure of these epitopes does not change after being separated from the primary complete one. The present achievements will lead to a better interpretation of the antigen-antibody interactions against gp60 in the designing process of safe and efficient vaccines.

Dataset Information

Structural and Epitope Analysis (T- and B-Cell Epitopes) of Hepatitis C Virus (HCV) Glycoproteins: An in silico Approach.

Publications

Structural and Epitope Analysis (T- and B-Cell Epitopes) of Hepatitis C Virus (HCV) Glycoproteins: An <i>in silico</i> Approach.

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