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

Marilia Rita Pinzone, D. Jake VanBelzen, Sam Weissman, Maria Paola Bertuccio, LaMont Cannon, Emmanuele Venanzi-Rullo, Stephen Migueles, R. Brad Jones, Talia Mota, Sarah B. Joseph, Kevin Groen, Alexander O. Pasternak, Wei-Ting Hwang, Brad Sherman, Anastasios Vourekas, Giuseppe Nunnari and Una O’Doherty ()
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Marilia Rita Pinzone: University of Pennsylvania
D. Jake VanBelzen: University of Pennsylvania
Sam Weissman: University of Pennsylvania
Maria Paola Bertuccio: University of Pennsylvania
LaMont Cannon: University of Pennsylvania
Emmanuele Venanzi-Rullo: University of Pennsylvania
Stephen Migueles: National Institutes of Health
R. Brad Jones: Weill Cornell Medical College
Talia Mota: Weill Cornell Medical College
Sarah B. Joseph: University of North Carolina at Chapel Hill
Kevin Groen: University of Amsterdam
Alexander O. Pasternak: University of Amsterdam
Wei-Ting Hwang: University of Pennsylvania
Brad Sherman: Leidos Biomedical Research Inc., supporting the Division of Clinical Research, NIAID
Anastasios Vourekas: University of Pennsylvania
Giuseppe Nunnari: University of Messina
Una O’Doherty: University of Pennsylvania

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-08431-7

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