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. 2020 Jul 6;12(7):731.
doi: 10.3390/v12070731.

In Silico Prediction of Human Leukocytes Antigen (HLA) Class II Binding Hepatitis B Virus (HBV) Peptides in Botswana

Wonderful Tatenda Choga  1   2 , Motswedi Anderson  1 , Edward Zumbika  3 , Bonolo B Phinius  1 , Tshepiso Mbangiwa  1   2 , Lynnette N Bhebhe  1 , Kabo Baruti  1   4 , Peter Opiyo Kimathi  5 , Kaelo K Seatla  1   6 , Rosemary M Musonda  1   7 , Trevor Graham Bell  8 , Sikhulile Moyo  1   7 , Jason T Blackard  9 , Simani Gaseitsiwe  1   7
Affiliations

In Silico Prediction of Human Leukocytes Antigen (HLA) Class II Binding Hepatitis B Virus (HBV) Peptides in Botswana

Wonderful Tatenda Choga et al. Viruses. .

Abstract

Hepatitis B virus (HBV) is the primary cause of liver-related malignancies worldwide, and there is no effective cure for chronic HBV infection (CHB) currently. Strong immunological responses induced by T cells are associated with HBV clearance during acute infection; however, the repertoire of epitopes (epi) presented by major histocompatibility complexes (MHCs) to elicit these responses in various African populations is not well understood. In silico approaches were used to map and investigate 15-mers HBV peptides restricted to 9 HLA class II alleles with high population coverage in Botswana. Sequences from 44 HBV genotype A and 48 genotype D surface genes (PreS/S) from Botswana were used. Of the 1819 epi bindings predicted, 20.2% were strong binders (SB), and none of the putative epi bind to all the 9 alleles suggesting that multi-epitope, genotype-based, population-based vaccines will be more effective against HBV infections as opposed to previously proposed broad potency epitope-vaccines which were assumed to work for all alleles. In total, there were 297 unique epi predicted from the 3 proteins and amongst, S regions had the highest number of epi (n = 186). Epitope-densities (Depi) between genotypes A and D were similar. A number of mutations that hindered HLA-peptide binding were observed. We also identified antigenic and genotype-specific peptides with characteristics that are well suited for the development of sensitive diagnostic kits. This study identified candidate peptides that can be used for developing multi-epitope vaccines and highly sensitive diagnostic kits against HBV infection in an African population. Our results suggest that viral variability may hinder HBV peptide-MHC binding, required to initiate a cascade of immunological responses against infection.

Keywords: Africa; Botswana; HLA class II alleles; T-cell epitopes; candidate multi-epitope vaccines (MEV); escape mutation; hepatitis B virus (HBV); immunoinformatics; in silico.

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Conflict of interest statement

All authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schema illustrating the flow of data analysis used in this study. N = sample size; SB = strong binding peptides; WB = weak biding peptides; Tepi = total predicted epitopes; PreS/S = HBV surface gene; Depi = epitope densities. Sequences were derived from patients with different clinical outcomes: −(HBV/HIV; CHB; OBI)—HIV = human immunodeficiency virus; OBI = occult hepatitis B infection, CHB = chronic hepatitis B infection, HBV/HIV = coinfection. The blue colored segment shows the pipeline used to evaluate the diversity of epi. The grey segment is the pipeline used to determine epi and measure of promiscuity and conservativeness. The pink segment is the pipeline used to determine the best candidate vaccine.
Figure 2
Figure 2
Epitope densities (Depi) of different PreS/S proteins stratified by genotype (A or D) and protein (PreS1, PreS2, S). Depi= ∑i=1nIepiTepi X Protein length where i can be any protein (PreS/SA versus PreS/SD). PreS1A represent genotype A large Hepatitis B surface antigen (HBsAg); PreS1D represent genotype D large HBsAg; PreS2A represent genotype A middle HBsAg; PreS2D represent genotype D middle HBsAg; SA represent genotype A small HBsAg; SD represent genotype D small HBsAg. Tepi = Total binding peptides (WB + SB). Nepi unique = count of unique binding peptides per each protein.
Figure 3
Figure 3
Showing a tertiary structure of candidate vaccines: (a) Tertiary structures of candidate epi modelled using 3Dpro webtool. The SA protein in (a) has the aa composition: 5′-SGFLGPLLVLQAGFFWYWGPSLYNILSPFIPLLPIFFCLWCIPIPSSWAFAKYLWEWASVRFSWLSLLVPFVQWF-3′, and had following theoretical properties: antigenicity (0.04), instability index (II = 47.07), estimated half-life in vitro = 1.9 h, molecular weight (mw) = 8878.62, aliphatic index (AI = 114.40) and grand average of hydrophobicity (GRAVY = 0.995), and theoretical alkalinity (pI = 7,76). Using VaxiJen ver2.0 server set at threshold of 0.4, the overall prediction for the protective antigen was 0.53, displaying it as a plausible antigen [66]. (b) (5′-MMWYWGPSLYSILSPFLPLLPIFFCLWSGFLGPLLVLQAGFFSWAFGKFLWEWASARFSWLSLLVPFVQWFTCPGYRWMCLRRFIIFLF-3′) protein modelled using from SD epi. The protein had following theoretical properties: antigenicity (0.11), instability index (II = 53), estimated half-life in vitro 30 h, molecular weight (mw) = 10749.99, aliphatic index (AI = 101.91) and grand average of hydrophobicity (GRAVY = 0.965), and theoretical alkalinity (pI = 9.42),). The antigenicity score predicted in both candidate vaccine suggests that they are plausible antigens [66].
Figure 3
Figure 3
Showing a tertiary structure of candidate vaccines: (a) Tertiary structures of candidate epi modelled using 3Dpro webtool. The SA protein in (a) has the aa composition: 5′-SGFLGPLLVLQAGFFWYWGPSLYNILSPFIPLLPIFFCLWCIPIPSSWAFAKYLWEWASVRFSWLSLLVPFVQWF-3′, and had following theoretical properties: antigenicity (0.04), instability index (II = 47.07), estimated half-life in vitro = 1.9 h, molecular weight (mw) = 8878.62, aliphatic index (AI = 114.40) and grand average of hydrophobicity (GRAVY = 0.995), and theoretical alkalinity (pI = 7,76). Using VaxiJen ver2.0 server set at threshold of 0.4, the overall prediction for the protective antigen was 0.53, displaying it as a plausible antigen [66]. (b) (5′-MMWYWGPSLYSILSPFLPLLPIFFCLWSGFLGPLLVLQAGFFSWAFGKFLWEWASARFSWLSLLVPFVQWFTCPGYRWMCLRRFIIFLF-3′) protein modelled using from SD epi. The protein had following theoretical properties: antigenicity (0.11), instability index (II = 53), estimated half-life in vitro 30 h, molecular weight (mw) = 10749.99, aliphatic index (AI = 101.91) and grand average of hydrophobicity (GRAVY = 0.965), and theoretical alkalinity (pI = 9.42),). The antigenicity score predicted in both candidate vaccine suggests that they are plausible antigens [66].
Figure 4
Figure 4
Pareto Analysis applied to rank the Tepi of alleles against their percentage frequency.
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