Una O’Doherty’s research group at the University of Pennsylvania has pioneered the development of tests to measure HIV DNA that is integrated into the genome of cells. The integration of HIV DNA presents a formidable obstacle to curing HIV infection, because it leads to the formation of a stable reservoir of infected cells that antiretroviral therapies cannot eradicate. HIV DNA can also exist in cells in an unintegrated form, but evidence indicates that this form degrades rapidly and does not persist. In a new paper in the journal Virology, O’Doherty and colleagues describe analyses designed to assess levels of unintegrated vs. integrated HIV DNA in a small group of individuals on ART with viral loads less than 75 copies for at least a year. The researchers report that three out of seven study participants showed sporadic excesses of the unintegrated form of HIV DNA compared to integrated DNA. They note that this result may indicate that a subset of individuals on ART experience sporadic low-level viral replication, which could contribute to the replenishment of their HIV reservoir. If confirmed, the findings will need to be taken into account by scientists working on approaches to curing HIV infection.
Virology. 2010 Oct 20. [Epub ahead of print]
Agosto LM, Liszewski MK, Mexas A, Graf E, Pace M, Yu JJ, Bhandoola A, O'Doherty U.
Graduate Program in Microbiology, Virology and Parasitology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Abstract
HIV establishes a latent reservoir early in infection that is resistant to anti-retroviral therapy and has a slow rate of decay. It is thought that the majority of HIV DNA in treated patients is integrated since unintegrated HIV DNA appears to be unstable. Thus, to monitor the HIV latent reservoir, total HIV DNA is commonly measured in PBMC from infected individuals. We investigated how often total approaches integrated HIV DNA in treated patients. To do this, we first assessed how accurate our integration assay is and determined the error in our measurements of total and integrated HIV DNA. We demonstrated an excess of total over integrated HIV DNA was present in a subset of patients, suggesting that measurements of total HIV DNA do not always correlate to the level of integration. Determining the cause of this excess and its frequency may have important implications for understanding HIV latent reservoir maintenance.
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