HIV reservoirs are dominated by genetically younger and clonally enriched proviruses

Characterizing the human immunodeficiency virus (HIV) reservoir that endures despite antiretroviral therapy (ART) is critical to cure efforts. We observed that the oldest proviruses persisting during ART were exclusively defective, while intact proviruses (and rebound HIV) dated to nearer ART initia...

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Bibliographic Details
Published in:mBio 2023-12, Vol.14 (6), p.e0241723
Main Authors: Kinloch, Natalie N, Shahid, Aniqa, Dong, Winnie, Kirkby, Don, Jones, Bradley R, Beelen, Charlotte J, MacMillan, Daniel, Lee, Guinevere Q, Mota, Talia M, Sudderuddin, Hanwei, Barad, Evan, Harris, Marianne, Brumme, Chanson J, Jones, R Brad, Brockman, Mark A, Joy, Jeffrey B, Brumme, Zabrina L
Format: Article
Language:English
Subjects:
genomic integrity
HIV reservoir
molecular dating
persistence
phylogenetics
proviral landscape
Research Article
Virology
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Summary:Characterizing the human immunodeficiency virus (HIV) reservoir that endures despite antiretroviral therapy (ART) is critical to cure efforts. We observed that the oldest proviruses persisting during ART were exclusively defective, while intact proviruses (and rebound HIV) dated to nearer ART initiation. This helps explain why studies that sampled sub-genomic proviruses on-ART (which are largely defective) routinely found sequences dating to early infection, whereas those that sampled replication-competent HIV found almost none. Together with our findings that intact proviruses were more likely to be clonal, and that on-ART low-level/isolated viremia originated from proviruses of varying ages (including possibly defective ones), our observations indicate that (i) on-ART and rebound viremia can have distinct within-host origins, (ii) intact proviruses have shorter lifespans than grossly defective ones and thus depend more heavily on clonal expansion for persistence, and (iii) an HIV reservoir predominantly "dating" to near ART initiation will be substantially adapted to within-host pressures, complicating immune-based cure strategies.
ISSN:2150-7511
2150-7511
DOI:10.1128/mbio.02417-23