Natural killer (NK) cell activity is regulated by target-cell recognition via polymorphic killer immunoglobulin-like receptors (KIRs). In Nature, Alter et al. show that HIV-infected people select for variant viruses with point mutations that enhance the interaction of inhibitory KIRs with infected CD4+ T cells. The HIV-1 genome has 22 sequence polymorphisms that can be associated with a specific inhibitory human KIR in HLA-C1+ people. For example, HIV-1 variants with viral protein U (Vpu) with methionine and histidine at positions 71 and 74, respectively, are significantly more prevalent in KIR2DL2+ patients, in contrast to HIV-1 variants with arginine and leucine at those positions, which are associated with KIR2DL2− patients. Cells infected with the former variant are more resistant to killing mediated by KIR2DL2+ NK cells but retain sensitivity to KIR2DL2− NK cells. Thus, NK cells can contribute to viral control, but this selective pressure leads to the outgrowth of viruses that can evade NK cell–mediated killing. It remains unclear how viral mutations lead to differences in KIR-HLA recognition.

Nature (4 Aug 2011) doi:10.1038/nature10237