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Nat Commun. 2019 Feb 13;10(1):728. doi: 10.1038/s41467-019-08431-7.

Longitudinal HIV sequencing reveals reservoir expression leading to decay which is obscured by clonal expansion.

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Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, 19104, PA, USA.
Department of Molecular Biosciences, Northwestern University, Evanston, 60201, IL, USA.
Department of Clinical and Experimental Medicine, Unit of Infectious Diseases, University of Messina, Messina, 98124, Italy.
Laboratory of Immunoregulation, National Institutes of Allergy & Infectious Diseases, National Institutes of Health, Bethesda, 20892, MD, USA.
Infectious Disease Division, Weill Cornell Medical College, New York, 10065, NY, USA.
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, USA.
Laboratory of Experimental Virology, Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, 1105, The Netherlands.
Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, 19104, PA, USA.
Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratories for Cancer Research, Leidos Biomedical Research Inc., supporting the Division of Clinical Research, NIAID, Frederick, 21702, MD, USA.
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, 19104, PA, USA.


After initiating antiretroviral therapy (ART), a rapid decline in HIV viral load is followed by a long period of undetectable viremia. Viral outgrowth assay suggests the reservoir continues to decline slowly. Here, we use full-length sequencing to longitudinally study the proviral landscape of four subjects on ART to investigate the selective pressures influencing the dynamics of the treatment-resistant HIV reservoir. We find intact and defective proviruses that contain genetic elements favoring efficient protein expression decrease over time. Moreover, proviruses that lack these genetic elements, yet contain strong donor splice sequences, increase relatively to other defective proviruses, especially among clones. Our work suggests that HIV expression occurs to a significant extent during ART and results in HIV clearance, but this is obscured by the expansion of proviral clones. Paradoxically, clonal expansion may also be enhanced by HIV expression that leads to splicing between HIV donor splice sites and downstream human exons.

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