TY - JOUR T1 - HIV persistence during antiviral therapy occurs due to cellular proliferation JF - bioRxiv DO - 10.1101/146977 SP - 146977 AU - Daniel B. Reeves AU - Elizabeth R. Duke AU - Thor A. Wagner AU - Sarah E. Palmer AU - Adam M. Spivak AU - Joshua T. Schiffer Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/06/07/146977.abstract N2 - Antiretroviral therapy (ART) suppresses most viral replication in HIV-infected persons, allowing a nearly normal lifespan. Yet, if ART is stopped, even after several decades of treatment, HIV levels typically rebound, and there is a high risk of progression to AIDS and death. While HIV replication re-emerges from a set of persistently infected memory CD4+ T cells following ART cessation, the mechanism for persistence remains controversial. One hypothesis maintains that HIV replicates and infects new cells continuously in anatomic microenvironments called ‘drug sanctuaries’ where ART drug concentrations are low. Alternatively, HIV infected cells may persist due to the natural longevity of memory CD4+ T cells. A final, non-mutually exclusive possibility is that latently infected CD4+ T cells frequently proliferate to maintain a relatively constant reservoir volume. Here we re-analyze existing data with ecologic methods and find that after one year of ART, at least 99% of remaining HIV infected cells originate via proliferation rather than infection. Next, using mathematical models, we demonstrate that even if a drug sanctuary is assumed, nearly all newly generated infected cells will arise from proliferation rather than new infection within 6 months of ART. Our results suggest that targeting proliferation of reservoir cells rather than HIV replication may be an optimal strategy for HIV eradication. ER -