We demonstrate that envelope differences selected in vivo allow SHIVs to adapt to the IFNα response; adapted HIV-1 variants encode IFNα resistant Envs, whereas Envs obtained directly from infected individuals early in their infection are sensitive, suggesting that IFNα may have an inhibitory effect on viruses spreading in humans that has not been observed through the study of adapted viruses. This evidence concerns the gene IFNA2 and infection.