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

Stefan Tenzer; Hayley Crawford; Phillip Pymm; Robert Gifford; Vattipally B Sreenu; Mirjana Weimershaus; Tulio de Oliveira; Anne Burgevin; Jan Gerstoft; Nadja Akkad; Daniel Lunn; Lars Fugger; John Bell; Hansjörg Schild; Peter van Endert; Astrid K N Iversen

doi:10.1016/j.celrep.2014.03.031

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

Stefan Tenzer, Hayley Crawford, Phillip Pymm, Robert Gifford, Vattipally B Sreenu, Mirjana Weimershaus, Tulio de Oliveira, Anne Burgevin, Jan Gerstoft, Nadja Akkad, Daniel Lunn, Lars Fugger, John Bell, Hansjörg Schild, Peter van Endert, Astrid K N Iversen

Department of Clinical Medicine

12 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Cell Reports
Volume	7
Issue number	2
Pages (from-to)	448-463
Number of pages	16
DOIs	https://doi.org/10.1016/j.celrep.2014.03.031
Publication status	Published - 24 Apr 2014

Keywords

Adaptation, Physiological
Africa, Southern
Amino Acid Sequence
Epitopes
Europe
Gene Frequency
HIV Infections
HIV-1
HLA-A1 Antigen
Humans
Immune Evasion
Molecular Sequence Data
Population
T-Lymphocytes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.celrep.2014.03.031

Cite this

Tenzer, S., Crawford, H., Pymm, P., Gifford, R., Sreenu, V. B., Weimershaus, M., de Oliveira, T., Burgevin, A., Gerstoft, J., Akkad, N., Lunn, D., Fugger, L., Bell, J., Schild, H., van Endert, P., & Iversen, A. K. N. (2014). HIV-1 Adaptation to Antigen Processing Results in Population-Level Immune Evasion and Affects Subtype Diversification. Cell Reports, 7(2), 448-463. https://doi.org/10.1016/j.celrep.2014.03.031

Tenzer, S, Crawford, H, Pymm, P, Gifford, R, Sreenu, VB, Weimershaus, M, de Oliveira, T, Burgevin, A, Gerstoft, J, Akkad, N, Lunn, D, Fugger, L, Bell, J, Schild, H, van Endert, P & Iversen, AKN 2014, 'HIV-1 Adaptation to Antigen Processing Results in Population-Level Immune Evasion and Affects Subtype Diversification', Cell Reports, vol. 7, no. 2, pp. 448-463. https://doi.org/10.1016/j.celrep.2014.03.031

@article{87beab15ed8e431d9f2652c7bbec9764,

title = "HIV-1 Adaptation to Antigen Processing Results in Population-Level Immune Evasion and Affects Subtype Diversification",

abstract = "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.",

keywords = "Adaptation, Physiological, Africa, Southern, Amino Acid Sequence, Epitopes, Europe, Gene Frequency, HIV Infections, HIV-1, HLA-A1 Antigen, Humans, Immune Evasion, Molecular Sequence Data, Population, T-Lymphocytes",

author = "Stefan Tenzer and Hayley Crawford and Phillip Pymm and Robert Gifford and Sreenu, {Vattipally B} and Mirjana Weimershaus and {de Oliveira}, Tulio and Anne Burgevin and Jan Gerstoft and Nadja Akkad and Daniel Lunn and Lars Fugger and John Bell and Hansj{\"o}rg Schild and {van Endert}, Peter and Iversen, {Astrid K N}",

year = "2014",

month = apr,

day = "24",

doi = "10.1016/j.celrep.2014.03.031",

language = "English",

volume = "7",

pages = "448--463",

journal = "Cell Reports",

issn = "2639-1856",

publisher = "Cell Press",

number = "2",

}

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

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

SN - 2639-1856

VL - 7

SP - 448

EP - 463

JO - Cell Reports

JF - Cell Reports

IS - 2

ER -

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

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this