Relationship between pre-existing viral reservoirs and the re-emergence of plasma viremia following discontinuation of highly active antiretroviral therapy

Tae-Wook Chun*, Richard T. Davey, Jr., Mario Ostrowski, Shawn J. Justement, Delphine Engel, James I. Mullins, H. Clifford Lane, and Anthony S. Fauci

Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892. Department of Microbiology, University of Washington, Seattle, Washington 98104.

The persistence of a pool of latently infected, resting CD4+ T cells carrying replication-competent HIV has been well documented in human immunodeficiency virus (HIV)-infected individuals who are receiving highly active antiretroviral therapy (HAART) and in whom successful suppression of plasma viremia has been achieved. This latent viral reservoir is considered to be a major impediment to complete eradication of HIV in infected individuals receiving HAART due to its long half-life and the ineffectiveness of currently available drugs in eliminating these infected cells; however, the pathogenic significance of this viral reservoir as well as its role in the rebound of plasma viremia following discontinuation of HAART is largely unknown. We have previously demonstrated that there was no correlation between the kinetics of viral rebound in plasma upon cessation of HAART and the size of the latent HIV reservoir prior to discontinuation of therapy in infected individuals in whom prolonged periods of successful suppression of plasma viremia had been achieved. Using heteroduplex mobility and tracking assays, we demonstrate in this study that the detectable pool of latently infected, resting CD4+ T cells does not account entirely for the early rebounding plasma HIV in infected individuals in whom HAART has been discontinued. The rebounding plasma virus was genetically distinct from both the cell-associated HIV RNA and replication-competent virus within the detectable pool of latently infected, resting CD4+ T cells in the majority of patients examined. These results suggest the existence of other persistent HIV reservoirs that could prompt rapid emergence of plasma viremia following cessation of HAART and underscore the necessity to develop therapies directed toward such populations of infected cells.


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