Kaslow et al. assesed the role of HLA class I alleles in HIV infection and found that HLA-B27 and B57 were strongly associated with slow progression to AIDS. Importantly, several independent studies have confirmed this finding, including a recent study that included more than 2700 patients with HIV infection. It is important to note, however, that HLA-B27 and B57 are not unique in their association with HIV control, but are rather extremes in an continuous spectrum of “protective” to “hazardous” HLA class I alleles. HLA-B27 is associated with low viral load and long-term non-progression in HIV infection as well as spontaneous clearance of hepatitis C infection. Recent studies linked protection by HLA-B27 in HIV and HCV infection to virological mechanisms such as complicated pathways of viral escape from immunodominant HLA-B27-restricted virus-specific CD 8 T cell epitopes. This virological mechanisms may help to explain why CD8 T cell responses targeting certain HIV and HCV-specific epitopes contribute to protection. However, they cannot explain why largely the same HLA class I alleles, including HLA-B27 and HLA-B57, are protective in unrelated viral infections.