Current understanding of the residual virus remaining in HIV-infected subjects on optimally effective antiretroviral therapy (ART) suggests that functional HIV cure will require either viral eradication or substantial viral reservoir reduction combined with potent, long-term anti-viral immunity such that any viral reactivation that occurs after ART cessation is eliminated or stringently controlled over a lifetime. Achieving this state might entail up to 4 mechanistically distinct interventions, including 1) induction of viral gene expression in the transcriptionally ‘quiescent’, latent HIV reservoir (allowing for immune targeting of these infected cells), 2) targeted immune destruction of all cells expressing HIV gene products, 3) establishment of a long-term potently antiviral immune response for immune surveillance after ART cessation, and 4) elimination of immunologic sanctuaries, such as the B follicular barrier for infected CD4+ T follicular helper T cells, that shield virally infected cells from immune destruction. Given the unproven benefits and potential risks of such interventions, there is a great need for an animal model that can be used for concept development and both pre-clinical safety and proof-of-concept studies. Our group has invested significant effort and resources in developing appropriate, state-of-the-art nonhuman primate models for such studies. In this talk, I will review the progress made in these models to both understand the immunobiology of ART-suppressed SIV infection and post-ART viral recrudescence and to develop therapeutic vaccination strategies that counter viral persistence and post-ART viral rebound.