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Studies of HIV-1 genetic diversity can provide clues on the effect of antiretroviral therapy (ART) on viral replication, the mechanisms for viral persistence, and the efficacy of new interventions. This article reviews methods for interrogating intrahost HIV-1 diversity, addresses the ongoing debate regarding HIV-1 compartmentalization and replication during ART, and summarizes recent findings on the effects of curative strategies on HIV-1 populations.HIV-1 replication in the blood is virtually halted upon the initiation of ART. However, proliferation of cells infected prior to ART provides a self-renewing reservoir for infection during ART. Current evidence supports that proliferation of infected cells is a mechanism for HIV-1 persistence in both the blood and the tissues. However, more studies are required to determine if tissue sanctuaries exist that may also allow viral replication during ART. Recent studies investigating potential curative interventions show little effect on the genetic landscape of HIV-1 infection and highlight the need to develop strategies targeting the proliferation of infected cells.Using phylogeny to characterize HIV-1 genetic diversity and evolution during ART has demonstrated a lack of viral replication, the proliferation of infected cells, and provides one metric to measure the effect of new interventions aimed at achieving a functional cure for HIV-1.