@article{83fea4092b3b40088bfb273f0a35893c,
title = "HIV-1 3'-Polypurine Tract Mutations Confer Dolutegravir Resistance by Switching to an Integration-Independent Replication Mechanism via 1-LTR Circles",
abstract = "Several recent studies indicate that mutations in the human immunodeficiency virus type 1 (HIV-1) 3'polypurine tract (3'PPT) motif can reduce sensitivity to the integrase inhibitor dolutegravir (DTG). Using an in vivo systematic evolution of ligands by exponential enrichment (SELEX) approach, we discovered that multiple different mutations in this viral RNA element can confer DTG resistance, suggesting that the inactivation of this critical reverse transcription element causes resistance. An analysis of the viral DNA products formed upon infection by these 3'PPT mutants revealed that they replicate without integration into the host cell genome, concomitant with an increased production of 1-LTR circles. As the replication of these virus variants is activated by the human T-lymphotropic virus 1 (HTLV-1) Tax protein, a factor that reverses epigenetic silencing of episomal HIV DNA, these data indicate that the 3'PPT-mutated viruses escape from the integrase inhibitor DTG by switching to an integration-independent replication mechanism.",
keywords = "antiretroviral agents, dolutegravir, drug resistance mechanisms, human immunodeficiency virus, retroviruses",
author = "Dekker, {Jos{\'e} G.} and Bep Klaver and Ben Berkhout and Das, {Atze T.}",
note = "Funding Information: Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number R01AI147330. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number R01AI147330. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank Bryan Cullen and Hal Bogard (Duke University Medical Center, Durham, North Carolina) for kindly providing us the CEM-SS cell line with doxycycline-controlled HTLV-1 Tax expression. Publisher Copyright: Copyright {\textcopyright} 2023 American Society for Microbiology. All Rights Reserved.",
year = "2023",
month = may,
day = "31",
doi = "https://doi.org/10.1128/jvi.00361-23",
language = "English",
volume = "97",
pages = "e0036123",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "5",
}