Journal of Antivirals & Antiretrovirals
Open Access
ISSN: 1948-5964
ISSN: 1948-5964
Mohammad Asif kahn
Scientific Tracks Abstracts: JAA
Background: West Nile virus (WNV) is a member of the genus Flavivirus, an important group of human viral pathogens that includes at least 64 species, with global distribution,including dengue, yellow fever, and several that cause encephalitis. Th e proteins of fl aviviruses are genetically related and contain many regions of the sequences that diff er by one or more amino acids. A greater understanding of the evolutionary conservation and variability of the viral proteomes is important to studies of the immune responses in the event of multiple Flavivirus infection, in particular those that co-circulate. Th is study was directed at the identifi cation and characterization of HLArestricted T-cell epitope peptides of the WNV proteome, with a focus on analysis of their specifi city,conservation, and variability in reported sequences of WNV and to other fl aviviruses. Methodology/Principal Findings: WN V HLA-restricted epitope peptides were identifi ed by use of H-2 defi cient transgenic mice, each expressing one of the six predominant HLA class I or II alleles, and immunized with 452 overlapping peptides spanning the entire WNV proteome. ELISpot assays revealed 137 peptides that elicited a peptide-specifi c T-cell response with an average frequency of about 7% of the peptides analyzed per allele. Th e evolutionary conservation and diversity of the 137 peptides relative to all reported WNV sequences in public databases were studied by use of Shannon?s entropy. Majority (~72%) of the epitope peptides were from highly conserved regions of the proteome (entropies < 0.7), and present in 88% or more of all recorded WNV sequences. Th e remaining ~12% contained minor intraspecies variants of the epitope, with each present in less than 1% of recorded WNVs. However, a principle fi nding of this study was that many of the conserved WNV epitope peptide sequences are highly shared with other fl aviviruses, including those that are major human pathogens. Only 51 of the 137 sequences identifi ed epitope peptides were WNV specifi c, while the majority (86) were shared with 64 other fl aviviruses, either as full-length or partial identical (_ 9 amino acids) sequences. Majority of these were present in a large fraction (_ 90%) of the recorded sequences of fl aviviruses with suffi cient data. Th e remaining 10% or less contained sequences highly similar to the epitope peptides with one or more amino acid diff erences. Sequences of the fl aviviruses that are fulllength/ partial identical or highly similar to the WNV epitope peptides are potential inter-species variants of the epitope, due to amino acid mismatches, either at the matching site or adjacent to it. Conclusions/Signifi cance: Th is study demonstrates the extensive presence in the WNV proteome of sequences that function in HLA binding and T-cell receptor (TCR) ligation and activation, and the widespread occurrence of variant sequences to these epitopes in a large number of other fl aviviruses. Th e fi nding that only 51 of the identifi ed 137 HLA-restricted WNV T-cell epitope peptides were specifi c to WNV and that all of the remainder were shared with many other fl aviviruses highlights the possible risk of exposure toT-cell receptor altered peptide ligands for subjects exposed to multiple fl aviviruses by infection or immunization, including the use of Flavivirus vector chimeras for delivery of DNA vaccines. Th e results suggest the use of pathogen-specifi c sequences rather than those based solely on evolutionary conservation in the design of newgeneration vaccines.