|Title||TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection.|
|Publication Type||Journal Article|
|Year of Publication||2012|
|Authors||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|
|Date Published||2012 Jul|
|Keywords||CD8-Positive T-Lymphocytes, Cells, Cultured, Epitopes, T-Lymphocyte, gag Gene Products, Human Immunodeficiency Virus, HIV Infections, HIV Long-Term Survivors, HIV-1, HLA-B Antigens, HLA-B27 Antigen, Humans, Perforin, Receptors, Antigen, T-Cell, Virus Replication|
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.
|Alternate Journal||Nat. Immunol.|