@article{9ce7e97b3f18434889a434262af33b91,
title = "Genetic complexity in the replication-competent latent HIV reservoir increases with untreated infection duration in infected youth",
abstract = "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.",
keywords = "HIV, genetic diversity, immune escape, latent reservoir, replication-competent, young adults, youth",
author = "Brumme, {Zabrina L.} and Hanwei Sudderuddin and Carrie Ziemniak and Katherine Luzuriaga and Jones, {Bradley R.} and Joy, {Jeffrey B.} and Cunningham, {Coleen K.} and Thomas Greenough and Deborah Persaud",
note = "Funding Information: the National Institute of Mental Health. Research was also funded in part by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number UM1AI126617, with co-funding support from the National Institute on Drug Abuse, the National Institute of Mental Health, and the National Institute of Neurological Disorders and Stroke (to D.P. and Z.L.B.), by the Canadian HIV Cure Enterprise Team Grant from the CIHR in partnership with CANFAR and the International AIDS Society (IAS) (HIG-133050 to Z.L.B.), by a project grant from the Canadian Institutes for Health Research (PJT-148621 to Z.L.B.), and a Simon Fraser University Next Big Question fund award (to Z.L.B.). Z.L.B. is supported by a Scholar Award from the Michael Smith Foundation for Health Research. C.K.C. is supported in part by the Duke University Center for AIDS Research (NIH 5P30 AI064518). Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH), all components of the National Institutes of Health (NIH), under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) and UM1AI106716 (IMPAACT LC), and by NICHD contract number HHSN275201800001I. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Funding Information: Funding: Research reported in this publication was funded by R01HD080474 to D.P and K.L. Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Network was provided by the National Institute of Allergy and Infectious Diseases (awards UM1AI068632, UM1AI068616, and UM1AI106716), the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and Publisher Copyright: {\textcopyright} 2018 Wolters Kluwer Health, Inc. All rights reserved.",
year = "2019",
month = feb,
day = "1",
doi = "10.1097/QAD.0000000000002045",
language = "English (US)",
volume = "33",
pages = "211--218",
journal = "AIDS",
issn = "0269-9370",
publisher = "Lippincott Williams and Wilkins",
number = "2",
}