TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection

Huabiao Chen; Zaza M. Ndhlovu; Dongfang Liu; Lindsay C. Porter; Justin W. Fang; Sam Darko; Mark A. Brockman; Toshiyuki Miura; Zabrina L. Brumme; Arne Schneidewind; Alicja Piechocka-Trocha; Kevin T. Cesa; Jennifer Sela; Thai D. Cung; Ildiko Toth; Florencia Pereyra; Xu G. Yu; Daniel C. Douek; Daniel E. Kaufmann; Todd M. Allen; Bruce D. Walker

doi:10.1038/ni.2342

TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection

Huabiao Chen, Zaza M. Ndhlovu, Dongfang Liu, Lindsay C. Porter, Justin W. Fang, Sam Darko, Mark A. Brockman, Toshiyuki Miura, Zabrina L. Brumme, Arne Schneidewind, Alicja Piechocka-Trocha, Kevin T. Cesa, Jennifer Sela, Thai D. Cung, Ildiko Toth, Florencia Pereyra, Xu G. Yu, Daniel C. Douek, Daniel E. Kaufmann, Todd M. AllenBruce D. Walker

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

Abstract

The human leukocyte antigens HLA-B*27 and HLA-B*57 are associated with protection against progression of disease that results from infection with human immunodeficiency virus type 1 (HIV-1), yet most people with alleles encoding HLA-B*27 and HLA-B*57 are unable to control HIV-1. Here we found that HLA-B*27-restricted CD8 ⁺ T cells in people able to control infection with HIV-1 (controllers) and those who progress to disease after infection with HIV-1 (progressors) differed in their ability to inhibit viral replication through targeting of the immunodominant epitope of group-associated antigen (Gag) of HIV-1. This was associated with distinct T cell antigen receptor (TCR) clonotypes, characterized by superior control of HIV-1 replication in vitro, greater cross-reactivity to epitope variants and enhanced loading and delivery of perforin. We also observed clonotype-specific differences in antiviral efficacy for an immunodominant HLA-B*57- restricted response in controllers and progressors. Thus, the efficacy of such so-called 'protective alleles' is modulated by specific TCR clonotypes selected during natural infection, which provides a functional explanation for divergent HIV-1 outcomes.

Original language	English (US)
Pages (from-to)	691-700
Number of pages	10
Journal	Nature Immunology
Volume	13
Issue number	7
DOIs	https://doi.org/10.1038/ni.2342
State	Published - Jul 2012
Externally published	Yes

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1038/ni.2342

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Chen, H., Ndhlovu, Z. M., Liu, D., Porter, L. C., Fang, J. W., Darko, S., Brockman, M. A., Miura, T., Brumme, Z. L., Schneidewind, A., Piechocka-Trocha, A., Cesa, K. T., Sela, J., Cung, T. D., Toth, I., Pereyra, F., Yu, X. G., Douek, D. C., Kaufmann, D. E., ... Walker, B. D. (2012). TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection. Nature Immunology, 13(7), 691-700. https://doi.org/10.1038/ni.2342

Chen, H, Ndhlovu, ZM, Liu, D, Porter, LC, Fang, JW, Darko, S, Brockman, MA, Miura, T, Brumme, ZL, Schneidewind, A, Piechocka-Trocha, A, Cesa, KT, Sela, J, Cung, TD, Toth, I, Pereyra, F, Yu, XG, Douek, DC, Kaufmann, DE, Allen, TM & Walker, BD 2012, 'TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection', Nature Immunology, vol. 13, no. 7, pp. 691-700. https://doi.org/10.1038/ni.2342

@article{d7cfdc669fe24772a96919fa8fef5978,

title = "TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection",

abstract = "The human leukocyte antigens HLA-B*27 and HLA-B*57 are associated with protection against progression of disease that results from infection with human immunodeficiency virus type 1 (HIV-1), yet most people with alleles encoding HLA-B*27 and HLA-B*57 are unable to control HIV-1. Here we found that HLA-B*27-restricted CD8 + T cells in people able to control infection with HIV-1 (controllers) and those who progress to disease after infection with HIV-1 (progressors) differed in their ability to inhibit viral replication through targeting of the immunodominant epitope of group-associated antigen (Gag) of HIV-1. This was associated with distinct T cell antigen receptor (TCR) clonotypes, characterized by superior control of HIV-1 replication in vitro, greater cross-reactivity to epitope variants and enhanced loading and delivery of perforin. We also observed clonotype-specific differences in antiviral efficacy for an immunodominant HLA-B*57- restricted response in controllers and progressors. Thus, the efficacy of such so-called 'protective alleles' is modulated by specific TCR clonotypes selected during natural infection, which provides a functional explanation for divergent HIV-1 outcomes.",

author = "Huabiao Chen and Ndhlovu, {Zaza M.} and Dongfang Liu and Porter, {Lindsay C.} and Fang, {Justin W.} and Sam Darko and Brockman, {Mark A.} and Toshiyuki Miura and Brumme, {Zabrina L.} and Arne Schneidewind and Alicja Piechocka-Trocha and Cesa, {Kevin T.} and Jennifer Sela and Cung, {Thai D.} and Ildiko Toth and Florencia Pereyra and Yu, {Xu G.} and Douek, {Daniel C.} and Kaufmann, {Daniel E.} and Allen, {Todd M.} and Walker, {Bruce D.}",

note = "Funding Information: We thank J. Wong (Massachusetts General Hospital) for monoclonal antibody 12F6 to CD3 and monoclonal antibody CD3:8 bispecific for CD3 and CD8; and all study participants for their contributions. Supported by the Harvard University Center for AIDS Research (5 P30 AI060354-04), the Bill and Melinda Gates Foundation (B.D.W. and D.C.D.), the Doris Duke Charitable Foundation (B.D.W.), the US National Institutes of Health (AI030914 to B.D.W. and AI074415 to T.M.A.), the Howard Hughes Medical Institute (B.D.W.), the Mark and Lisa Schwartz Foundation (B.D.W.), the Intramural Research Program and the Office of AIDS Research of the US National Institutes of Health (D.C.D. and S.D.), the Canadian Institutes for Health Research (New Investigator Award to Z.L.B.) and the Canada Research Chair in Viral Pathogenesis and Immunity (M.A.B.).",

year = "2012",

month = jul,

doi = "10.1038/ni.2342",

language = "English (US)",

volume = "13",

pages = "691--700",

journal = "Nature Immunology",

issn = "1529-2908",

publisher = "Nature Publishing Group",

number = "7",

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TY - JOUR

T1 - TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection

AU - Chen, Huabiao

AU - Ndhlovu, Zaza M.

AU - Liu, Dongfang

AU - Porter, Lindsay C.

AU - Fang, Justin W.

AU - Darko, Sam

AU - Brockman, Mark A.

AU - Miura, Toshiyuki

AU - Brumme, Zabrina L.

AU - Schneidewind, Arne

AU - Piechocka-Trocha, Alicja

AU - Cesa, Kevin T.

AU - Sela, Jennifer

AU - Cung, Thai D.

AU - Toth, Ildiko

AU - Pereyra, Florencia

AU - Yu, Xu G.

AU - Douek, Daniel C.

AU - Kaufmann, Daniel E.

AU - Allen, Todd M.

AU - Walker, Bruce D.

N1 - Funding Information: We thank J. Wong (Massachusetts General Hospital) for monoclonal antibody 12F6 to CD3 and monoclonal antibody CD3:8 bispecific for CD3 and CD8; and all study participants for their contributions. Supported by the Harvard University Center for AIDS Research (5 P30 AI060354-04), the Bill and Melinda Gates Foundation (B.D.W. and D.C.D.), the Doris Duke Charitable Foundation (B.D.W.), the US National Institutes of Health (AI030914 to B.D.W. and AI074415 to T.M.A.), the Howard Hughes Medical Institute (B.D.W.), the Mark and Lisa Schwartz Foundation (B.D.W.), the Intramural Research Program and the Office of AIDS Research of the US National Institutes of Health (D.C.D. and S.D.), the Canadian Institutes for Health Research (New Investigator Award to Z.L.B.) and the Canada Research Chair in Viral Pathogenesis and Immunity (M.A.B.).

PY - 2012/7

Y1 - 2012/7

N2 - The human leukocyte antigens HLA-B*27 and HLA-B*57 are associated with protection against progression of disease that results from infection with human immunodeficiency virus type 1 (HIV-1), yet most people with alleles encoding HLA-B*27 and HLA-B*57 are unable to control HIV-1. Here we found that HLA-B*27-restricted CD8 + T cells in people able to control infection with HIV-1 (controllers) and those who progress to disease after infection with HIV-1 (progressors) differed in their ability to inhibit viral replication through targeting of the immunodominant epitope of group-associated antigen (Gag) of HIV-1. This was associated with distinct T cell antigen receptor (TCR) clonotypes, characterized by superior control of HIV-1 replication in vitro, greater cross-reactivity to epitope variants and enhanced loading and delivery of perforin. We also observed clonotype-specific differences in antiviral efficacy for an immunodominant HLA-B*57- restricted response in controllers and progressors. Thus, the efficacy of such so-called 'protective alleles' is modulated by specific TCR clonotypes selected during natural infection, which provides a functional explanation for divergent HIV-1 outcomes.

AB - The human leukocyte antigens HLA-B*27 and HLA-B*57 are associated with protection against progression of disease that results from infection with human immunodeficiency virus type 1 (HIV-1), yet most people with alleles encoding HLA-B*27 and HLA-B*57 are unable to control HIV-1. Here we found that HLA-B*27-restricted CD8 + T cells in people able to control infection with HIV-1 (controllers) and those who progress to disease after infection with HIV-1 (progressors) differed in their ability to inhibit viral replication through targeting of the immunodominant epitope of group-associated antigen (Gag) of HIV-1. This was associated with distinct T cell antigen receptor (TCR) clonotypes, characterized by superior control of HIV-1 replication in vitro, greater cross-reactivity to epitope variants and enhanced loading and delivery of perforin. We also observed clonotype-specific differences in antiviral efficacy for an immunodominant HLA-B*57- restricted response in controllers and progressors. Thus, the efficacy of such so-called 'protective alleles' is modulated by specific TCR clonotypes selected during natural infection, which provides a functional explanation for divergent HIV-1 outcomes.

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JO - Nature Immunology

JF - Nature Immunology

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ER -

TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection

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