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HIV-1 Drug Resistance to Integrase Strand Transfer Inhibitors in HIV-1 Non-B Subtypes

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Western University Scholarship@Western Electronic Thesis and Dissertation Repository 4-20-2021 12:00 PM HIV-1 Drug Resistance to Integrase Strand Transfer Inhibitors in HIV-1 non-B Subtypes Emmanuel Ndashimye, The University of Western Ontario Supervisor: Arts, Eric J., The University of Western Ontario A thesis submitted in partial fulfillment of the equirr ements for the Doctor of Philosophy degree in Microbiology and Immunology © Emmanuel Ndashimye 2021 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Infectious Disease Commons, Medical Immunology Commons, Medical Microbiology Commons, Medical Molecular Biology Commons, Medical Pharmacology Commons, Virology Commons, and the Virus Diseases Commons Recommended Citation Ndashimye, Emmanuel, "HIV-1 Drug Resistance to Integrase Strand Transfer Inhibitors in HIV-1 non-B Subtypes" (2021). Electronic Thesis and Dissertation Repository. 7765. https://ir.lib.uwo.ca/etd/7765 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. Abstract Human immunodeficiency syndrome (HIV-1) has infected over 75 million people and over 35 million have succumbed to virus related illnesses. Despite access to a variety of antiretroviral therapy (ART) options, ART programs have been disproportionally spread in the world with low- and middle-income countries (LMICs) facing challenges to access the most potent ART options. With less potent ART remaining in use in LMICs, HIV-1 drug resistance (HIVDR) presents a growing challenge in LMICs. Since approval of the first-generation integrase strand transfer inhibitor (INSTIs), Raltegravir (RAL) in 2007, INSTIs remain the best choice as a backbone of ART. Access to second generation INSTIs, Dolutegravir (DTG) and bictegravir (BIC) in LMICs is based on need and not on a full evaluation of the effectiveness of these treatments in patients infected with non-B HIV-1 subtypes. To address this challenge of limited INSTIs associated HIVDR data in non-B HIV subtypes, we first screened for the presence of INSTIs associated drug resistance mutations (DRMs) in ART naïve and experienced patients in Uganda using Sanger and Illumina sequencing. In Uganda, 47% of patients failing on RAL carry resistance to RAL-and elvitegravir (EVG), and only 4% harbor resistant virus to DTG. A panel of recombinant viruses from patient-derived HIV-1 integrases carrying resistant mutations was created and tested for susceptibility to a panel of INSTIs: EVG, RAL, DTG, BIC, and CAB. The virus carrying N155H or Y143R/S was susceptible to DTG, BIC, and CAB but highly resistant to RAL and EVG (>50- fold change). Two patients, one with E138A/G140A/Q148R/G163R and one with E138K/G140A/S147G/Q148K, displayed the highest reported resistance to RAL, EVG (FC, >1000) and even DTG (FC, >100), BIC (FC, 60->100), and CAB (FC, 429->1000). All viruses had impaired replication fitness and <50% reduction in integration capacity. We further determined potential novel polymorphisms associated with INSTI resistance in HIV-1 subtype A and D using simple vector machine analysis. The identified I208L and I203M, did not show reduced susceptibility to RAL or DTG with 1.3-1.8-fold and 1-1.4-fold observed, respectively. Further investigation is required to determine how these novel mutations influence susceptibility to INSTIs in HIV-1 subtype A and D infected patients. ii Keywords HIV-1 non-subtype B, integrase strand transfer inhibitors, HIV-1 drug resistance, Low-and Middle-income countries, Uganda iii Summary for Lay Audience Human immunodeficiency syndrome virus type 1 (HIV-1) is the causative agent for Acquired immunodeficiency syndrome (AIDS) which is characterized by rapid depletion of CD4+ T cells which eventually results in emergence of opportunistic infections. HIV-1 like other retroviruses, hijack host DNA machinery to be able to replicate and cause havoc in the infected individual. Because of high replication rate and numerous errors during replication, there are diverse strains of HIV-1 circulating in world population which are commonly referred to as subtypes, circulating recombinant forms, and unique recombinant forms. The non-B HIV-1 subtypes are predominantly in low- and middle-income countries (LMICs) and account for up to ~ 90% of HIV-1 infections. The antiretroviral therapy (ART) has tremendously improved the lives of individuals infected with HIV-1 and discovery of an even more potent class of ART, the integrase strand transfer inhibitors (INSTIs) has further improved HIV-1 treatment outcomes. Despite these advances, research of HIV-1 drug resistance associated with INSTIs has historically been done in HIV-1 subtype B virus which is predominant in high-income countries. With improved access to INSTIs by HIV-1 patients in LMICs, there is urgent need to assess susceptibility of HIV-1 non-B strains to INSTIs and also discover novel potential pathways to resistance in these strains. From a cohort of HIV-1 infected patients in Uganda, we show that prolonged virological failure on INSTI, raltegravir, leads to accumulation of drug resistance mutations which confer resistance to all currently available INSTIs. Novel mutations in the HIV-1 integrase gene which show no impact on INSTIs susceptibility by themselves, may act as secondary mutations to other drug resistance mutations outside HIV-1 integrase gene which merits further investigation. iv Co-Authorship Statement I am the sole lead author of the first three manuscripts presented in this work. Though I am the second author in the fourth manuscript, I carried out much of the work presented including, sample collection, laboratory assays, participated in data analysis, and writing of the manuscript. Other co-authors of the manuscript each had a role in the study including designing of experiments, recruitment of patients, data analysis, writing and providing critical reviews of the manuscript. The authors list for the co-authored manuscript; Mariano Avino, Emmanuel Ndashimye, Daniel J. Lizotte, Abayomi S. Olabode, Richard, M. Gibson, Adam A. Meadows, Cissy M. Kityo, Eva Nabulime, Fred Kyeyune, Immaculate Nankya, Miguel E. Quin˜ones-Mateu, Eric J. Arts, Art F. Y. Poon. v Acknowledgments To my great supervisor and mentor, Dr Eric Arts, I very much appreciate the opportunity to learn from you and for making me the person I am today. Thank you for being more than a supervisor but also a great friend. I’m so grateful for your never-ending dedication, guidance, facilitation, and effort to make this work possible. My sincere gratitude also goes to my supervisory committee members, Dr Steve Barr, and Dr Michael Silverman for guiding me while undertaking the program. A special appreciation goes to the HIV-1 drug resistance teams in Uganda, Canada, and New Zealand which include Dr Miguel E. Quiñones-Mateu, Dr Art F.Y Poon, Dr Immaculate Nankya, Dr Fred Kyeyune, Dr Mariano Avino, and Dr Abayomi Samuel Olabode, for the fruitful collaborations which has made this work possible and as such helped in enhancing HIV-1 treatment research. The members of Dr Eric Arts, Jamie Mann, Yong Gao, Jessica Prodger, and Ryan Troyer laboratories at Western University, are all highly appreciated for sincere support, guidance, and encouragements. To my dear family, mother, Epiphanie Mpumugeni; father, Sylvester Nsengivunva; sister, Florence Uwamaliya; brothers, Ronald Hakiza, Olivier Ishimwe Rukundo, and Leon Ineza; thank you all for the support, encouragement, and love. You all sacrificed a lot for me and for that I will forever be grateful. Finally, to my loving wife, Enid Nayebare; children, Ethan Ndashimye, and Eli Ndashimye, thank you very much for bearing my frequent absence and standing with me as I went through this journey. May the good Lord continue to bless you and grant you good health. vi Table of Contents Abstract ............................................................................................................................. ii Summary for Lay Audience ............................................................................................. iv Co-Authorship Statement.................................................................................................. v Acknowledgments............................................................................................................ vi Table of Contents ............................................................................................................ vii List of Tables ................................................................................................................... xi List of Figures ................................................................................................................ xiii List of Appendices ......................................................................................................... xvi List of abbreviations ..................................................................................................... xvii Chapter 1 ........................................................................................................................... 1 1 Introduction .................................................................................................................. 1 1.1 HIV-1 ...................................................................................................................
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