Molecular basis for selection and inhibition of HIV-1 escape virus by T cells and KIR2DL2+NK cells

Takayuki Chikata; Kimiko Kuroki; Nozomi Kuse; Anna E. Kliszczak; Wayne Paes; Nanami Tomioka; Robert Parker; Aure Aflalo; Tomohiro Akahoshi; Yu Zhang; Ryoya Yamashita; Ryuma Sakata; Hiroki Kusaka; Yosuke Watanabe; Annalisa Nicastri; Haruki Matsubara; Toyoyuki Ose; Shunsuke Kita; Shinichi Oka; Hiroyuki Gatanaga; Zhansong Lin; Nicola Ternette; Persephone Borrow; Katsumi Maenaka; Masafumi Takiguchi

doi:10.1038/s41467-025-64768-2

Molecular basis for selection and inhibition of HIV-1 escape virus by T cells and KIR2DL2⁺NK cells

Takayuki Chikata
, Kimiko Kuroki
, Nozomi Kuse
, Anna E. Kliszczak
, Wayne Paes
, Nanami Tomioka
, Robert Parker
, Aure Aflalo
, Tomohiro Akahoshi
, Yu Zhang
, Ryoya Yamashita
, Ryuma Sakata
, Hiroki Kusaka
, Yosuke Watanabe
, Annalisa Nicastri
, Haruki Matsubara
, Toyoyuki Ose
, Shunsuke Kita
, Shinichi Oka
, Hiroyuki Gatanaga

Zhansong Lin, Nicola Ternette, Persephone Borrow (Lead / Corresponding author), Katsumi Maenaka (Lead / Corresponding author), Masafumi Takiguchi (Lead / Corresponding author)

Cell Signalling and Immunology

Research output: Contribution to journal › Article › peer-review

Abstract

NK cells and CD8⁺ T cells both contribute to HIV-1 control. These cells not only suppress HIV-1 replication, but also select HIV-1 escape mutant viruses. Most viruses bearing T cell escape mutations are expected to remain susceptible to NK cell suppression, but their inhibition by NK cells is unclear. We investigated the role of HIV-1-specific CD8⁺ T cells and NK cells recognizing superimposed Pol peptides in selection and control of HIV-1 mutant virus. KIR2DL2⁺NK cells have an enhanced ability to recognize HIV-1-infected cells after selection of Pol mutant virus by PolIY11-specific HLA-C*12:02-restricted T cells. Mass spectrometry-based immunopeptidome profiling of HIV-1-infected cells and analysis of crystal structures of TCR- and KIR2DL2-HLA-C*12:02-peptide complexes demonstrate the molecular basis for selection and recognition of the escape mutant epitope by TCR and KIR2DL2. The present study elucidates the mechanism for selection and inhibition of an HIV-1 escape virus by T cells and NK cells.

Original language	English
Article number	9796
Number of pages	16
Journal	Nature Communications
Volume	16
DOIs	https://doi.org/10.1038/s41467-025-64768-2
Publication status	Published - 6 Nov 2025

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General
General Physics and Astronomy

UN SDGs

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

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Final Published VersionFinal published version, 3.09 MBLicence: CC BY-NC-ND

Cite this

Chikata, T., Kuroki, K., Kuse, N., Kliszczak, A. E., Paes, W., Tomioka, N., Parker, R., Aflalo, A., Akahoshi, T., Zhang, Y., Yamashita, R., Sakata, R., Kusaka, H., Watanabe, Y., Nicastri, A., Matsubara, H., Ose, T., Kita, S., Oka, S., ... Takiguchi, M. (2025). Molecular basis for selection and inhibition of HIV-1 escape virus by T cells and KIR2DL2⁺NK cells. Nature Communications, 16, Article 9796. https://doi.org/10.1038/s41467-025-64768-2

@article{b8f39619acde4b7b920bb06216e11f0c,

title = "Molecular basis for selection and inhibition of HIV-1 escape virus by T cells and KIR2DL2+NK cells",

abstract = "NK cells and CD8+ T cells both contribute to HIV-1 control. These cells not only suppress HIV-1 replication, but also select HIV-1 escape mutant viruses. Most viruses bearing T cell escape mutations are expected to remain susceptible to NK cell suppression, but their inhibition by NK cells is unclear. We investigated the role of HIV-1-specific CD8+ T cells and NK cells recognizing superimposed Pol peptides in selection and control of HIV-1 mutant virus. KIR2DL2+NK cells have an enhanced ability to recognize HIV-1-infected cells after selection of Pol mutant virus by PolIY11-specific HLA-C*12:02-restricted T cells. Mass spectrometry-based immunopeptidome profiling of HIV-1-infected cells and analysis of crystal structures of TCR- and KIR2DL2-HLA-C*12:02-peptide complexes demonstrate the molecular basis for selection and recognition of the escape mutant epitope by TCR and KIR2DL2. The present study elucidates the mechanism for selection and inhibition of an HIV-1 escape virus by T cells and NK cells.",

author = "Takayuki Chikata and Kimiko Kuroki and Nozomi Kuse and Kliszczak, \{Anna E.\} and Wayne Paes and Nanami Tomioka and Robert Parker and Aure Aflalo and Tomohiro Akahoshi and Yu Zhang and Ryoya Yamashita and Ryuma Sakata and Hiroki Kusaka and Yosuke Watanabe and Annalisa Nicastri and Haruki Matsubara and Toyoyuki Ose and Shunsuke Kita and Shinichi Oka and Hiroyuki Gatanaga and Zhansong Lin and Nicola Ternette and Persephone Borrow and Katsumi Maenaka and Masafumi Takiguchi",

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year = "2025",

month = nov,

day = "6",

doi = "10.1038/s41467-025-64768-2",

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Chikata, T, Kuroki, K, Kuse, N, Kliszczak, AE, Paes, W, Tomioka, N, Parker, R, Aflalo, A, Akahoshi, T, Zhang, Y, Yamashita, R, Sakata, R, Kusaka, H, Watanabe, Y, Nicastri, A, Matsubara, H, Ose, T, Kita, S, Oka, S, Gatanaga, H, Lin, Z, Ternette, N, Borrow, P, Maenaka, K & Takiguchi, M 2025, 'Molecular basis for selection and inhibition of HIV-1 escape virus by T cells and KIR2DL2⁺NK cells', Nature Communications, vol. 16, 9796. https://doi.org/10.1038/s41467-025-64768-2

TY - JOUR

T1 - Molecular basis for selection and inhibition of HIV-1 escape virus by T cells and KIR2DL2+NK cells

AU - Chikata, Takayuki

AU - Kuroki, Kimiko

AU - Kuse, Nozomi

AU - Kliszczak, Anna E.

AU - Paes, Wayne

AU - Tomioka, Nanami

AU - Parker, Robert

AU - Aflalo, Aure

AU - Akahoshi, Tomohiro

AU - Zhang, Yu

AU - Yamashita, Ryoya

AU - Sakata, Ryuma

AU - Kusaka, Hiroki

AU - Watanabe, Yosuke

AU - Nicastri, Annalisa

AU - Matsubara, Haruki

AU - Ose, Toyoyuki

AU - Kita, Shunsuke

AU - Oka, Shinichi

AU - Gatanaga, Hiroyuki

AU - Lin, Zhansong

AU - Ternette, Nicola

AU - Borrow, Persephone

AU - Maenaka, Katsumi

AU - Takiguchi, Masafumi

PY - 2025/11/6

Y1 - 2025/11/6

N2 - NK cells and CD8+ T cells both contribute to HIV-1 control. These cells not only suppress HIV-1 replication, but also select HIV-1 escape mutant viruses. Most viruses bearing T cell escape mutations are expected to remain susceptible to NK cell suppression, but their inhibition by NK cells is unclear. We investigated the role of HIV-1-specific CD8+ T cells and NK cells recognizing superimposed Pol peptides in selection and control of HIV-1 mutant virus. KIR2DL2+NK cells have an enhanced ability to recognize HIV-1-infected cells after selection of Pol mutant virus by PolIY11-specific HLA-C*12:02-restricted T cells. Mass spectrometry-based immunopeptidome profiling of HIV-1-infected cells and analysis of crystal structures of TCR- and KIR2DL2-HLA-C*12:02-peptide complexes demonstrate the molecular basis for selection and recognition of the escape mutant epitope by TCR and KIR2DL2. The present study elucidates the mechanism for selection and inhibition of an HIV-1 escape virus by T cells and NK cells.

AB - NK cells and CD8+ T cells both contribute to HIV-1 control. These cells not only suppress HIV-1 replication, but also select HIV-1 escape mutant viruses. Most viruses bearing T cell escape mutations are expected to remain susceptible to NK cell suppression, but their inhibition by NK cells is unclear. We investigated the role of HIV-1-specific CD8+ T cells and NK cells recognizing superimposed Pol peptides in selection and control of HIV-1 mutant virus. KIR2DL2+NK cells have an enhanced ability to recognize HIV-1-infected cells after selection of Pol mutant virus by PolIY11-specific HLA-C*12:02-restricted T cells. Mass spectrometry-based immunopeptidome profiling of HIV-1-infected cells and analysis of crystal structures of TCR- and KIR2DL2-HLA-C*12:02-peptide complexes demonstrate the molecular basis for selection and recognition of the escape mutant epitope by TCR and KIR2DL2. The present study elucidates the mechanism for selection and inhibition of an HIV-1 escape virus by T cells and NK cells.

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DO - 10.1038/s41467-025-64768-2

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SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

M1 - 9796

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