Epitope length variants balance protective immune responses and viral escape in HIV-1 infection
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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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 110449 |
| Tidsskrift | Cell Reports |
| Vol/bind | 38 |
| Udgave nummer | 9 |
| Antal sider | 22 |
| ISSN | 2211-1247 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
We thank the patients for donating samples, Bente Baadegaard and Lene Pors Jensen for patient management, Dorthe Hass for expert technical assistance, E. Yvonne Jones for access to facilities, support, and helpful discussions, and Jamie Rossjohn for helpful discussions. This work was supported by the Medical Research Fund at Oxford University (HM1090) (A.K.N.I.), the Oak Foundation (OFIL-20-095) (A.K.N.I.), the Genomes2Vaccines (STREP), FP6, contract number LSHB-CT-2003-503231 (P.v.E.), the Hochschulbau-förderungsgesetz Program ( HBFG-122-605 ) (S.T. and H.S.), the German Research Foundation ( CRC 1292 , TP13 , and Z01 ) and the Forschungszentrum für Immuntherapie (FZI) Mainz (S.T. and H.S.). D.A.P. is a Wellcome Trust Senior Investigator (100326/Z/12/Z).
Funding Information:
We thank the patients for donating samples, Bente Baadegaard and Lene Pors Jensen for patient management, Dorthe Hass for expert technical assistance, E. Yvonne Jones for access to facilities, support, and helpful discussions, and Jamie Rossjohn for helpful discussions. This work was supported by the Medical Research Fund at Oxford University (HM1090) (A.K.N.I.), the Oak Foundation (OFIL-20-095) (A.K.N.I.), the Genomes2Vaccines (STREP), FP6, contract number LSHB-CT-2003-503231 (P.v.E.), the Hochschulbau-förderungsgesetz Program (HBFG-122-605) (S.T. and H.S.), the German Research Foundation (CRC 1292, TP13, and Z01) and the Forschungszentrum für Immuntherapie (FZI) Mainz (S.T. and H.S.). D.A.P. is a Wellcome Trust Senior Investigator (100326/Z/12/Z). A.K.N.I. conceived, designed, and managed the study; P.P. S.T. E.W. M.W. A.B. S.K. M.H. and A.K.N.I. performed experiments; S.T. H.S. P.v.E. M.H. and A.K.N.I. planned and supervised experiments; P.P. S.T. P.v.E. M.H. and A.K.N.I. analyzed data; P.P. T.M.J. and M.H. performed structural modeling; J.G. and A.K.N.I. provided patient samples; K.L. J.E.M. V.A. D.A.P. L.F. J.I.B. H.S. P.v.E. and A.K.N.I. provided reagents; A.K.N.I. and P.P. wrote the manuscript; D.A.P. P.v.E. and M.H. provided intellectual input; and A.K.N.I. and D.A.P. edited the final manuscript. All authors commented on the manuscript prior to submission. The authors declare no competing interests.
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© 2022 The Author(s)
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