PDBsum entry 4qrp

Immune system

PDB id: 4qrp

Contents

Protein chains

276 a.a.

99 a.a.

203 a.a.

243 a.a.

Ligands

HIS-SER-LYS-LYS-LYS-CYS-ASP-GLU-LEU ×2

Metals

IOD ×12

_NA ×3

Waters ×56

References listed in PDB file

Key reference

• Title: An extensive antigenic footprint underpins immunodominant tcr adaptability against a hypervariable viral determinant.
• Authors: U.K.Nivarthi, S.Gras, L.Kjer-Nielsen, R.Berry, I.S.Lucet, J.J.Miles, S.L.Tracy, A.W.Purcell, D.S.Bowden, M.Hellard, J.Rossjohn, J.Mccluskey, M.Bharadwaj.
• Ref.: J Immunol, 2014, 193, 5402-5413. [DOI no: 10.4049/jimmunol.1401357]
• PubMed id: 25355921

Abstract

Mutations in T cell epitopes are implicated in hepatitis C virus (HCV) persistence and can impinge on vaccine development. We recently demonstrated a narrow bias in the human TCR repertoire targeted at an immunodominant, but highly mutable, HLA-B*0801-restricted epitope ((1395)HSKKKCDEL(1403) [HSK]). To investigate if the narrow TCR repertoire facilitates CTL escape, structural and biophysical studies were undertaken, alongside comprehensive functional analysis of T cells targeted at the natural variants of HLA-B*0801-HSK in different HCV genotypes and quasispecies. Interestingly, within the TCR-HLA-B*0801-HSK complex, the TCR contacts all available surface-exposed residues of the HSK determinant. This broad epitope coverage facilitates cross-genotypic reactivity and recognition of common mutations reported in HCV quasispecies, albeit to a varying degree. Certain mutations did abrogate T cell reactivity; however, natural variants comprising these mutations are reportedly rare and transient in nature, presumably due to fitness costs. Overall, despite a narrow bias, the TCR accommodated frequent mutations by acting like a blanket over the hypervariable epitope, thereby providing effective viral immunity. Our findings simultaneously advance the understanding of anti-HCV immunity and indicate the potential for cross-genotype HCV vaccines.