TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection.
The human leukocyte antigens HLA-B27 and HLA-B57 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-B27 and HLA-B57 are unable to control HIV-1. Here we found that HLA-B27-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-B57-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.
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston, Massachusetts, USA.
Huabiao
H
Chen
Zaza M
ZM
Ndhlovu
Dongfang
D
Liu
Lindsay C
LC
Porter
Justin W
JW
Fang
Sam
S
Darko
Mark A
MA
Brockman
Toshiyuki
T
Miura
Zabrina L
ZL
Brumme
Arne
A
Schneidewind
Alicja
A
Piechocka-Trocha
Kevin T
KT
Cesa
Jennifer
J
Sela
Thai D
TD
Cung
Ildiko
I
Toth
Florencia
F
Pereyra
Xu G
XG
Yu
Daniel C
DC
Douek
Daniel E
DE
Kaufmann
Todd M
TM
Allen
Bruce D
BD
Walker
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015658:HIV Infections / Q000097:blood / Q000276:immunology* / Q000821:virology; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000276:immunology*; D015235:HLA-B Antigens / Q000276:immunology*; D015796:HLA-B27 Antigen / Q000276:immunology*; D006801:Humans; D054353:Perforin / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D014779:Virus Replication / Q000276:immunology; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology
D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; D015796:HLA-B27 Antigen; C103707:HLA-B57 antigen; D011948:Receptors, Antigen, T-Cell; D054301:gag Gene Products, Human Immunodeficiency Virus; D054353:Perforin