West Nile Virus T-Cell Ligand Sequences Shared with Other Flaviviruses: a Multitude of Variant Sequences as Potential Altered Peptide Ligands

Abstract

West Nile virus (WNV), a member of the genus Flavivirus, is a mosquito-borne RNA pathogen closely related to numerous other flaviviruses of the Japanese encephalitis (JE) group, and to a lesser degree to Dengue virus (DENV), Yellow fever virus (YFV), and several other flaviviruses of about 70 different species (5, 18). The genome is a positive-sense, single-stranded RNA of approximately 10,293 nucleotides encoding a polyprotein of approximately 3,430 amino acids (aa) that is cleaved to produce three structural proteins, capsid (C), precursor membrane (prM), and envelope (E), and seven nonstructural (NS) proteins, NS1, 2a, 2b,3, 4a, 4b, and 5 (24,37). Originally isolated in Africa in 1937 (62), WNV has become an increasingly important human pathogen widely endemic in Africa, Asia, Europe, and North America and a significant agent of viral encephalitis (28,38,45). WNV and several of the major human pathogen flaviviruses are known to cocirculate (28, 71); for example, WNV and St. Louis encephalitis virus (LEV) in North America; WNV, DENV, and Japanese encephalitis virus (JEV) around the Indian subcontinent and portions of Southeast Asia (SEA); and WNV, DENV, JEV, and Murray Valley encephalitis virus (MVE) in neighboring pockets of SEA and Australasia.The widespread colocalization of WNV with other flaviviruses calls for a greater understanding of the phylogenetic relatedness and possible pathophysiologic associations of flaviviruses. We previously reported a large-scale analysis of the conservation and variability of overlapping nonamers, the typical length of human leukocyte antigen (HLA) class I or class II binding cores of T-cell epitopes (47), of the 2,746 WNV protein sequences collected from the NCBI Entrez Protein Database (17). Notably, of the 88 completely conserved sequence fragments identified, representing 34% of the WNV proteome, 67 were also present in many other flaviviruses with identities of nine or more amino acids. These sequence homologies called attention to a broad inter-Flavivirus risk of altered peptide ligands (APL) (58), T-cell epitopes with one or more amino acid differences, that possibly would result in modified immune responses in the event of exposure to multiple Flavivirus pathogens.This study focused on analyses of the diversity and presence in

Identification of Conserved and HLA Promiscuous DENV3 T-Cell Epitopes

“…The number of epitopes found on HLA class II TgM outnumbered the HLA class I counterpart, which is consistent with other studies using the same TgM animal model and similar immunization strategies [53], [67]. The combination of immunization strategy (with peptide pool), the difference in topology between HLA class I and II molecules and the HLA class I epitope processing mechanism [68] might explain the reasons for the paucity of HLA class I epitopes identified in our study and, thus, revealing to be a caveat for identification of HLA class I restricted epitopes.…”

Identification of CDCA1‐derived long peptides bearing both CD4+ and CD8+ T‐cell epitopes: CDCA1‐specific CD4+ T‐cell immunity in cancer patients

“…HLA‐A2 (HHD) and HLA‐A24 (HHH) transgenic mice (Tgm) were kindly provided by Dr. F.A. Lemonnier . Mice were intradermally injected at the base of the tail with CDCA1‐LP (HLA‐A2 Tgm, 50 µg/mouse; HLA‐A24 Tgm 100 µg/mouse) emulsified in incomplete Freund's adjuvant (IFA) at 7‐day intervals.…”

A Hydrogen Peroxide-Inactivated Virus Vaccine Elicits Humoral and Cellular Immunity and Protects against Lethal West Nile Virus Infection in Aged Mice

“…Priming of a potent cellular immune response against a human HLA-restricted WNV epitope suggests that H 2 O 2 -WNV-KUNV might stimulate a protective CD8 ϩ T cell response in humans. In support of this, profiling studies from WNV-infected patients have shown that multiple CD8 ϩ T cell epitopes map to the structural proteins of WNV and are presented by different MHC class I alleles (42,54,63,64). Future immunization studies in other HLA transgenic mice and, ultimately, humans will be required to define the extent of antigen-specific CD8 ϩ T cell responses generated after H 2 O 2 -WNV-KUNV administration.…”