TY - JOUR

T1 - HIV-1 Adaptation to Antigen Processing Results in Population-Level Immune Evasion and Affects Subtype Diversification

AU - Tenzer, Stefan

AU - Crawford, Hayley

AU - Pymm, Phillip

AU - Gifford, Robert

AU - Sreenu, Vattipally B

AU - Weimershaus, Mirjana

AU - de Oliveira, Tulio

AU - Burgevin, Anne

AU - Gerstoft, Jan

AU - Akkad, Nadja

AU - Lunn, Daniel

AU - Fugger, Lars

AU - Bell, John

AU - Schild, Hansjörg

AU - van Endert, Peter

AU - Iversen, Astrid K N

N1 - Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2014/4/24

Y1 - 2014/4/24

N2 - The recent HIV-1 vaccine failures highlight the need to better understand virus-host interactions. One key question is why CD8(+) T cell responses to two HIV-Gag regions are uniquely associated with delayed disease progression only in patients expressing a few rare HLA class I variants when these regions encode epitopes presented by ~30 more common HLA variants. By combining epitope processing and computational analyses of the two HIV subtypes responsible for ~60% of worldwide infections, we identified a hitherto unrecognized adaptation to the antigen-processing machinery through substitutions at subtype-specific motifs. Multiple HLA variants presenting epitopes situated next to a given subtype-specific motif drive selection at this subtype-specific position, and epitope abundances correlate inversely with the HLA frequency distribution in affected populations. This adaptation reflects the sum of intrapatient adaptations, is predictable, facilitates viral subtype diversification, and increases global HIV diversity. Because low epitope abundance is associated with infrequent and weak T cell responses, this most likely results in both population-level immune evasion and inadequate responses in most people vaccinated with natural HIV-1 sequence constructs. Our results suggest that artificial sequence modifications at subtype-specific positions in vitro could refocus and reverse the poor immunogenicity of HIV proteins.

AB - The recent HIV-1 vaccine failures highlight the need to better understand virus-host interactions. One key question is why CD8(+) T cell responses to two HIV-Gag regions are uniquely associated with delayed disease progression only in patients expressing a few rare HLA class I variants when these regions encode epitopes presented by ~30 more common HLA variants. By combining epitope processing and computational analyses of the two HIV subtypes responsible for ~60% of worldwide infections, we identified a hitherto unrecognized adaptation to the antigen-processing machinery through substitutions at subtype-specific motifs. Multiple HLA variants presenting epitopes situated next to a given subtype-specific motif drive selection at this subtype-specific position, and epitope abundances correlate inversely with the HLA frequency distribution in affected populations. This adaptation reflects the sum of intrapatient adaptations, is predictable, facilitates viral subtype diversification, and increases global HIV diversity. Because low epitope abundance is associated with infrequent and weak T cell responses, this most likely results in both population-level immune evasion and inadequate responses in most people vaccinated with natural HIV-1 sequence constructs. Our results suggest that artificial sequence modifications at subtype-specific positions in vitro could refocus and reverse the poor immunogenicity of HIV proteins.

KW - Adaptation, Physiological

KW - Africa, Southern

KW - Amino Acid Sequence

KW - Epitopes

KW - Europe

KW - Gene Frequency

KW - HIV Infections

KW - HIV-1

KW - HLA-A1 Antigen

KW - Humans

KW - Immune Evasion

KW - Molecular Sequence Data

KW - Population

KW - T-Lymphocytes

U2 - 10.1016/j.celrep.2014.03.031

DO - 10.1016/j.celrep.2014.03.031

M3 - Journal article

C2 - 24726370

VL - 7

SP - 448

EP - 463

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 2

ER -