Abstract
Failure of protease-inhibitor (PI)-based second-line antiretroviral therapy (ART) with medication adherence but no protease drug resistance mutations (DRMs) is not well understood. This study investigated the involvement of gp41 and gag as alternative mechanisms, not captured by conventional resistance testing and particularly relevant in resource-limited settings where third-line ART is limited. We evaluated gp41 and gag for unique amino acids in seven subtype A infected Kenyans failing second-line therapy with no PI resistance yet detectable lopinavir (query dataset), compared to seven similar-setting patients with PI resistance or undetectable lopinavir and 69 publically available subtype A Kenyan whole-genomes sequences. Three gp41 (607T, 641L, 721I) and four gag (124S, 143V, 339P, 357S) amino acids were significantly more frequent in the query dataset compared to the other datasets, with significantly high co-occurrence. The genotypic analysis of a unique group of HIV-1 subtype A infected patients, identified seven amino acids that could potentially contribute to a multi-gene mechanism of PI-based ART failure in the absence of PI DR mutations.
References
Jun 6, 2007·Current HIV/AIDS Reports·David R BangsbergSteven G Deeks
Aug 20, 2008·Bone Marrow Transplantation·L M O'ConnorE Conneally
May 18, 2011·Proceedings of the National Academy of Sciences of the United States of America·Valerie F BoltzJohn W Mellors
Aug 23, 2011·AIDS·Babafemi TaiwoUNKNOWN ACTG A5262 Team
Sep 29, 2011·PloS One·Jade GhosnMarie-Laure Chaix
Oct 14, 2011·Viruses·Akbar AliCelia A Schiffer
Feb 9, 2012·AIDS·Olawale AjoseNathan Ford
Aug 8, 2012·Retrovirology·Axel FunMonique Nijhuis
Sep 4, 2012·Nature Medicine·Daniel I S RosenbloomMartin A Nowak
Oct 9, 2012·The Journal of Biological Chemistry·Sook-Kyung LeeRonald Swanstrom
May 25, 2013·The Journal of Infectious Diseases·Mina C HosseinipourJean B Nachega
Aug 28, 2013·The Journal of Clinical Investigation·S Alireza RabiRobert F Siliciano
Feb 3, 2016·Antimicrobial Agents and Chemotherapy·Jennifer GiandhariLynn Morris
May 28, 2016·Journal of the International AIDS Society·Katherine BrooksRami Kantor
Nov 3, 2016·Proceedings of the National Academy of Sciences of the United States of America·Lalit DeshmukhG Marius Clore
Dec 3, 2016·Scientific Reports·Katherine A SutherlandRavindra K Gupta
Citations
Jul 31, 2018·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Jennifer A ThompsonUNKNOWN Europe Africa Research Network for Evaluation of Second-line Therapy (EARNEST) Trial Team
Aug 23, 2018·AIDS·Rami KantorLameck Diero
Feb 16, 2019·The Journal of Antimicrobial Chemotherapy·Marine PerrierCharlotte Charpentier
Feb 7, 2019·The Journal of Antimicrobial Chemotherapy·R DatirR K Gupta
Nov 5, 2020·MBio·Rawlings DatirRavindra K Gupta
Jan 14, 2021·MBio·Yuta HikichiEric O Freed