HIV-1 replicates well in humans but not in atypical host species, which has limited the development of animal models for AIDS. This study now shows that HIV-1 adapts to replicate efficiently and cause AIDS in pig-tailed macaques. The animals were inoculated with HIV-1 and treated with a CD8-specific antibody to cause transient CD8+ T cell depletion. Serial animal-to-animal infection resulted in persistently high viraemia and decreased CD4+ T cell counts in the blood and gut-associated lymphoid tissue, as well as immune activation and Pneumocystis pneumonia, which is indicative of HIV-1-induced pathogenesis and progression to AIDS. Host adaptation of the virus was conferred by four amino acid deletions in the envelope gene, which is associated with co-receptor switching, and mutations in Vpu, which contribute to the ability of the virus to antagonize the host restriction factor tetherin. Further development of this animal model will facilitate the study of HIV-1 therapies and vaccines.