Within the initial weeks following transmission, HIV-1 becomes well established in the lymphatic tissue reservoir. Replication of the virus occurs throughout the course of infection despite the induction of a vigorous adaptive immune response by the host. The emergence of variants with particular characteristics correlates with increased viral burden and disease progression, indicating that the fitness of the infecting virus and selected variants plays a significant role in persistent viral replication and disease progression. This article reviews studies of HIV-1 variants and pathogenicity. It focuses mainly on experimental SIV infection of macaques as a model system to decipher the significance of viral variants for infection, persistence, and disease because it is difficult to systematically examine transmission and pathogenesis of HIV-1 in humans.