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

被引:193
作者
Chen, Huabiao [1 ,2 ,3 ]
Ndhlovu, Zaza M. [1 ,2 ,3 ]
Liu, Dongfang [1 ,2 ]
Porter, Lindsay C. [1 ,2 ]
Fang, Justin W. [1 ,2 ]
Darko, Sam [4 ]
Brockman, Mark A. [1 ,2 ,5 ]
Miura, Toshiyuki [1 ,2 ,6 ]
Brumme, Zabrina L. [1 ,2 ,5 ]
Schneidewind, Arne [1 ,2 ,7 ]
Piechocka-Trocha, Alicja [1 ,2 ,3 ]
Cesa, Kevin T. [1 ,2 ]
Sela, Jennifer [1 ,2 ]
Cung, Thai D. [1 ,2 ]
Toth, Ildiko [1 ,2 ]
Pereyra, Florencia [1 ,2 ]
Yu, Xu G. [1 ,2 ]
Douek, Daniel C. [4 ]
Kaufmann, Daniel E. [1 ,2 ]
Allen, Todd M. [1 ,2 ]
Walker, Bruce D. [1 ,2 ,3 ]
机构
[1] Massachusetts Gen Hosp, MIT, Ragon Inst, Boston, MA 02114 USA
[2] Harvard Univ, Boston, MA 02115 USA
[3] Howard Hughes Med Inst, Chevy Chase, MD USA
[4] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA
[5] Simon Fraser Univ, Fac Hlth Sci, Burnaby, BC V5A 1S6, Canada
[6] Univ Tokyo, Inst Med Sci, Tokyo, Japan
[7] Univ Hosp Regensburg, Dept Internal Med, Regensburg, Germany
基金
美国国家卫生研究院;
关键词
IMMUNODEFICIENCY-VIRUS TYPE-1; CD8(+) T-CELLS; VIRAL LOAD; ELITE CONTROLLERS; REPLICATION CAPACITY; DISEASE PROGRESSION; LYMPHOCYTE ESCAPE; IMMUNE CONTROL; RESPONSES; EPITOPE;
D O I
10.1038/ni.2342
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:691 / +
页数:12
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