We have recently demonstrated the potent effect of HCMV co-infection in shaping the NK cell repertoire during chronic HIV-1 infection, leading to an accelerated differentiation and adaptive reconfiguration of the NK cell compartment and expansion of an NK cell subset expressing NKG2C, the activating counterpart of NKG2A that also binds to HLA-E (recognizing HLA-E bound to HLA class Ia signal sequence peptides with lower affinity than NKG2A) (13–15). The gene discussed is HLA-E; the disease is HIV-1 infection.