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Genetic complexity in the replication-competent latent HIV reservoir increases with untreated infection duration in infected youth

Brumme, Zabrina L.a,b; Sudderuddin, Hanweia; Ziemniak, Carriec; Luzuriaga, Katherined; Jones, Bradley R.b,e; Joy, Jeffrey B.b,e; Cunningham, Coleen K.f; Greenough, Thomasd; Persaud, Deborahc

doi: 10.1097/QAD.0000000000002045

Objective: Timely initiation of combination antiretroviral therapy (ART) limits latent HIV reservoir size and should also limit reservoir genetic complexity. However, the relationship between these two factors remains unclear, particularly among HIV-infected youth.

Design: Retrospective analysis of replication-competent latent HIV clones serially isolated by limiting-dilution culture from resting CD4+ T-cell reservoirs from ART-suppressed, young adult participants of a historic phase I therapeutic vaccine trial (PACTG/IMPAACT-P1059).

Methods: Replication-competent latent HIV clones isolated from resting CD4+ T cells of four perinatally and 10 nonperinatally infected young adults (average 22 versus 6 years uncontrolled infection, respectively) were sequenced in Pol and Nef. Within-host HIV sequence datasets were characterized with respect to their genetic diversity and inferred immune escape mutation burden.

Results: Although participants were comparable in terms of sociodemographic and HIV sampling characteristics (e.g. on average, a mean 17 Pol sequences were recovered at five timepoints over up to 70 weeks) and the length of ART suppression at study entry (average 3 years), replication-competent HIV reservoir size, genetic diversity, immune escape mutation burden and variant complexity were significantly higher among the perinatally infected participants who experienced longer durations of uncontrolled viremia. Nevertheless, viral sequences inferred to retain susceptibility to host cellular immune responses were detected in all participants, irrespective of uncontrolled viremia duration.

Conclusion: HIV elimination in late-suppressed youth may be doubly challenged by larger and more genetically complex reservoirs. Strategies that integrate host and viral genetic complexity to achieve HIV remission or cure may merit consideration in such cases.

aFaculty of Health Sciences, Simon Fraser University, Burnaby

bBC Centre for Excellence in HIV/AIDS, Vancouver, Canada

cJohns Hopkins University School of Medicine, Baltimore

dUniversity of Massachusetts Medical School, Worcester, USA

eDepartment of Medicine, University of British Columbia, Vancouver, Canada

fDuke University Medical Center, Durham, North Carolina, USA.

Correspondence to Zabrina L. Brumme, PhD, Associate Professor, Faculty of Health Sciences, Simon Fraser University, Burnaby, BC V5A 1S6, Canada, and Deborah Persaud, MD, Professor of Pediatrics, Johns Hopkins University School of Medicine and Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 200 North Wolfe Street, Baltimore, MD, 21205, USA. Z.B.: Tel: +1 778 782 8872; fax: +1 778 782 5927; e-mail: and D.P.: Tel: +1 443 287 3733; e-mail:

Received 17 July, 2018

Accepted 13 September, 2018

Copyright © 2019 Wolters Kluwer Health, Inc.