The HLA class I alleles HLA-B*27 and HLA-B*57 are associated with resistance to certain viral infections, but the mechanisms that underlie this have remained obscure. In Nature Medicine, Horton and colleagues identify a means by which HLA-B*27 and HLA-B*57 convey resistance to human immunodeficiency virus (HIV). Chronic infection with viruses such as HIV is characterized by T cell expression of the receptor Tim-3, which mediates suppression by regulatory T cells (Treg cells) via the counter-ligand galectin-9 and leads to immune exhaustion. The function of Treg cells in HLA-B*27 and HLA-B*57 people is intrinsically normal, but their HIV-specific cytotoxic T lymphocytes show lower activation-induced upregulation of Tim-3 than do those from people of other haplotypes. Furthermore, HLA-B*27- and HLA-B*57-restricted cytotoxic T lymphocytes activated by HIV epitopes can kill Treg cells in a granzyme B–dependent manner. Therefore, HLA-B*27 and HLA-B*57 may confer resistance to virus-mediated exhaustion in a twofold way directed at the inhibition of Treg cell function.

Nat. Med. 17, 989–995 (2011)