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

• DOI: 10.1038/ni.2342
• Publication Date: 2012-06-10T17:55:45Z
• Authors: 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-...; 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
• Keywords: Perforin; Receptors, Antigen, T-Cell; Epitopes, T-Lymphocyte; HIV Infections; CD8-Positive T-Lymphocytes; Virus Replication; gag Gene Products, Human Immunodeficiency Virus; HIV Long-Term Survivors; 3. Good health; HLA-B Antigens; HIV-1; Humans; Cells, Cultured; HLA-B27 Antigen

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.