Epitope length variants balance protective immune responses and viral escape in HIV-1 infection

Phillip Pymm; Stefan Tenzer; Edmund Wee; Mirjana Weimershaus; Anne Burgevin; Simon Kollnberger; Jan Gerstoft; Tracy M. Josephs; Kristin Ladell; James E. McLaren; Victor Appay; David A. Price; Lars Fugger; John I. Bell; Hansjörg Schild; Peter van Endert; Maria Harkiolaki; Astrid K.N. Iversen

doi:10.1016/j.celrep.2022.110449

Epitope length variants balance protective immune responses and viral escape in HIV-1 infection

Phillip Pymm, Stefan Tenzer, Edmund Wee, Mirjana Weimershaus, Anne Burgevin, Simon Kollnberger, Jan Gerstoft, Tracy M. Josephs, Kristin Ladell, James E. McLaren, Victor Appay, David A. Price, Lars Fugger, John I. Bell, Hansjörg Schild, Peter van Endert, Maria Harkiolaki, Astrid K.N. Iversen^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

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Abstract

Cytotoxic T lymphocyte (CTL) and natural killer (NK) cell responses to a single optimal 10-mer epitope (KK10) in the human immunodeficiency virus type-1 (HIV-1) protein p24Gag are associated with enhanced immune control in patients expressing human leukocyte antigen (HLA)-B^∗27:05. We find that proteasomal activity generates multiple length variants of KK10 (4–14 amino acids), which bind TAP and HLA-B^∗27:05. However, only epitope forms ≥8 amino acids evoke peptide length-specific and cross-reactive CTL responses. Structural analyses reveal that all epitope forms bind HLA-B^∗27:05 via a conserved N-terminal motif, and competition experiments show that the truncated epitope forms outcompete immunogenic epitope forms for binding to HLA-B^∗27:05. Common viral escape mutations abolish (L136M) or impair (R132K) production of KK10 and longer epitope forms. Peptide length influences how well the inhibitory NK cell receptor KIR3DL1 binds HLA-B^∗27:05 peptide complexes and how intraepitope mutations affect this interaction. These results identify a viral escape mechanism from CTL and NK responses based on differential antigen processing and peptide competition.

Original language	English
Article number	110449
Journal	Cell Reports
Volume	38
Issue number	9
Number of pages	22
ISSN	2211-1247
DOIs	https://doi.org/10.1016/j.celrep.2022.110449
Publication status	Published - 2022

Bibliographical note

Publisher Copyright:
© 2022 The Author(s)

Keywords

crystal structures
cytotoxic T lymphocytes
differential antigen processing
HIV-1
HLA-B27:05
immune-response inhibition
KIR3DL1
natural killer cells
peptide competition
viral escape

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Pymm, P., Tenzer, S., Wee, E., Weimershaus, M., Burgevin, A., Kollnberger, S., Gerstoft, J., Josephs, T. M., Ladell, K., McLaren, J. E., Appay, V., Price, D. A., Fugger, L., Bell, J. I., Schild, H., van Endert, P., Harkiolaki, M., & Iversen, A. K. N. (2022). Epitope length variants balance protective immune responses and viral escape in HIV-1 infection. Cell Reports, 38(9), [110449]. https://doi.org/10.1016/j.celrep.2022.110449

Epitope length variants balance protective immune responses and viral escape in HIV-1 infection. / Pymm, Phillip; Tenzer, Stefan; Wee, Edmund; Weimershaus, Mirjana; Burgevin, Anne; Kollnberger, Simon; Gerstoft, Jan; Josephs, Tracy M.; Ladell, Kristin; McLaren, James E.; Appay, Victor; Price, David A.; Fugger, Lars; Bell, John I.; Schild, Hansjörg; van Endert, Peter; Harkiolaki, Maria; Iversen, Astrid K.N.

In: Cell Reports, Vol. 38, No. 9, 110449, 2022.

Research output: Contribution to journal › Journal article › Research › peer-review

Pymm, P, Tenzer, S, Wee, E, Weimershaus, M, Burgevin, A, Kollnberger, S, Gerstoft, J, Josephs, TM, Ladell, K, McLaren, JE, Appay, V, Price, DA, Fugger, L, Bell, JI, Schild, H, van Endert, P, Harkiolaki, M & Iversen, AKN 2022, 'Epitope length variants balance protective immune responses and viral escape in HIV-1 infection', Cell Reports, vol. 38, no. 9, 110449. https://doi.org/10.1016/j.celrep.2022.110449

Pymm, Phillip ; Tenzer, Stefan ; Wee, Edmund ; Weimershaus, Mirjana ; Burgevin, Anne ; Kollnberger, Simon ; Gerstoft, Jan ; Josephs, Tracy M. ; Ladell, Kristin ; McLaren, James E. ; Appay, Victor ; Price, David A. ; Fugger, Lars ; Bell, John I. ; Schild, Hansjörg ; van Endert, Peter ; Harkiolaki, Maria ; Iversen, Astrid K.N. / Epitope length variants balance protective immune responses and viral escape in HIV-1 infection. In: Cell Reports. 2022 ; Vol. 38, No. 9.

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abstract = "Cytotoxic T lymphocyte (CTL) and natural killer (NK) cell responses to a single optimal 10-mer epitope (KK10) in the human immunodeficiency virus type-1 (HIV-1) protein p24Gag are associated with enhanced immune control in patients expressing human leukocyte antigen (HLA)-B∗27:05. We find that proteasomal activity generates multiple length variants of KK10 (4–14 amino acids), which bind TAP and HLA-B∗27:05. However, only epitope forms ≥8 amino acids evoke peptide length-specific and cross-reactive CTL responses. Structural analyses reveal that all epitope forms bind HLA-B∗27:05 via a conserved N-terminal motif, and competition experiments show that the truncated epitope forms outcompete immunogenic epitope forms for binding to HLA-B∗27:05. Common viral escape mutations abolish (L136M) or impair (R132K) production of KK10 and longer epitope forms. Peptide length influences how well the inhibitory NK cell receptor KIR3DL1 binds HLA-B∗27:05 peptide complexes and how intraepitope mutations affect this interaction. These results identify a viral escape mechanism from CTL and NK responses based on differential antigen processing and peptide competition.",

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AU - Tenzer, Stefan

AU - Wee, Edmund

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AU - Burgevin, Anne

AU - Kollnberger, Simon

AU - Gerstoft, Jan

AU - Josephs, Tracy M.

AU - Ladell, Kristin

AU - McLaren, James E.

AU - Appay, Victor

AU - Price, David A.

AU - Fugger, Lars

AU - Bell, John I.

AU - Schild, Hansjörg

AU - van Endert, Peter

AU - Harkiolaki, Maria

AU - Iversen, Astrid K.N.

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N2 - Cytotoxic T lymphocyte (CTL) and natural killer (NK) cell responses to a single optimal 10-mer epitope (KK10) in the human immunodeficiency virus type-1 (HIV-1) protein p24Gag are associated with enhanced immune control in patients expressing human leukocyte antigen (HLA)-B∗27:05. We find that proteasomal activity generates multiple length variants of KK10 (4–14 amino acids), which bind TAP and HLA-B∗27:05. However, only epitope forms ≥8 amino acids evoke peptide length-specific and cross-reactive CTL responses. Structural analyses reveal that all epitope forms bind HLA-B∗27:05 via a conserved N-terminal motif, and competition experiments show that the truncated epitope forms outcompete immunogenic epitope forms for binding to HLA-B∗27:05. Common viral escape mutations abolish (L136M) or impair (R132K) production of KK10 and longer epitope forms. Peptide length influences how well the inhibitory NK cell receptor KIR3DL1 binds HLA-B∗27:05 peptide complexes and how intraepitope mutations affect this interaction. These results identify a viral escape mechanism from CTL and NK responses based on differential antigen processing and peptide competition.

AB - Cytotoxic T lymphocyte (CTL) and natural killer (NK) cell responses to a single optimal 10-mer epitope (KK10) in the human immunodeficiency virus type-1 (HIV-1) protein p24Gag are associated with enhanced immune control in patients expressing human leukocyte antigen (HLA)-B∗27:05. We find that proteasomal activity generates multiple length variants of KK10 (4–14 amino acids), which bind TAP and HLA-B∗27:05. However, only epitope forms ≥8 amino acids evoke peptide length-specific and cross-reactive CTL responses. Structural analyses reveal that all epitope forms bind HLA-B∗27:05 via a conserved N-terminal motif, and competition experiments show that the truncated epitope forms outcompete immunogenic epitope forms for binding to HLA-B∗27:05. Common viral escape mutations abolish (L136M) or impair (R132K) production of KK10 and longer epitope forms. Peptide length influences how well the inhibitory NK cell receptor KIR3DL1 binds HLA-B∗27:05 peptide complexes and how intraepitope mutations affect this interaction. These results identify a viral escape mechanism from CTL and NK responses based on differential antigen processing and peptide competition.

KW - crystal structures

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KW - immune-response inhibition

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KW - natural killer cells

KW - peptide competition

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