HIV-1 integrase strand transfer inhibitor resistance to dolutegravir, bictegravir and cabotegravir
department or school: Medicine, Faculty of
department or school: Medicine, Department of
data provider: DSpace
degree campus: UBCV
creator: Zhang, Wendy W.
issued: 2023-01-05T21:55:58Z
issued: 2022
related degree: Master of Science - MSc
degree grantor: University of British Columbia
description: Antiretroviral drugs are basis of the treatment of human immunodeficiency virus (HIV) infections. Combined antiretroviral therapy (ART) uses a combination of three antiretroviral drugs to inhibit viral replication and to prevent disease progression and has become a global standard for HIV treatment. Integrase strand transfer inhibitors (INSTIs) are the most recent class of antiretroviral drugs to reach the market. INSTIs function by inhibiting the 3’-processing ability of HIV integrase and preventing the incorporation of the HIV genome into the host’s deoxyribonucleic acid (DNA). The use of raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG) in clinical settings has increased since their approval, however there is a risk that the development of drug resistance would impact the treatment of the individual as well as the general population in the event of transmitted drug resistance. New integrase inhibitors, bictegravir (BIC) and cabotegravir (CAB), has been recently approve and has reached late phases of development, respectively. Due to the novelty of INSTIs, less is known about INSTI resistance than other drug classes that pre-date INSTIs. The main objectives discussed in this thesis are 1) the direct comparison of the effect of DTG, BIC and CAB on viruses harbouring known major INSTI mutations and 2) the development of a panel of patient-derived recombinant viruses with INSTI resistance with matched genotypes and phenotypes and the assessment of resistance to new INSTIs using recombinant viruses from the database. The resistance profiles of a set of patient-derived recombinant viruses harbouring the major mutations G140S/Q148H on its own and in combination with additional amino acid substitutions was determined for DTG, BIC and CAB. As a follow-up, a larger panel of recombinant viruses with unique permutations of amino acid substitutions in the integrase gene were generated using a limiting dilution PCR procedure. The resulting panel was assessed for INS…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/83587
note: HIV-1 INTEGRASE STRAND TRANSFER INHIBITOR RESISTANCE TO DOLUTEGRAVIR, BICTEGRAVIR AND CABOTEGRAVIR by Wendy W. Zhang BSc. The University of British Columbia, 2014 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE In THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Experimental Medicine) THE UNIVERISTY OF BRITISH COLUMBIA (Vancouver) December 2022 ã Wendy W. Zhang, 2022 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, a thesis entitled: HIV-1 integrase strand transfer inhibitor resistance to dolutegravir, bictegravir and cabotegravir submitted by Wendy Wenyu Zhang in partial fulfillment of the requirements for the degree of Master of Science in Experimental Medicine Examining Committee: Dr. P. Richard Harrigan, Professor, Medicine, UBC Supervisor Dr. Jeffery Joy, Assistant Professor, Medicine, UBC Supervisory Committee Member Dr. Helene Côté, Professor, Pathology and Laboratory Medicine, UBC Supervisory Committee Member Muhammad Morshed, Clinical Professor, Pathology, UBC Additional Examiner iii Abstract Antiretroviral drugs are basis of the treatment of human immunodeficiency virus (HIV) infections. Combined antiretroviral therapy (ART) uses a combination of three antiretroviral drugs to inhibit viral replication and to prevent disease progression and has become a global standard for HIV treatment. Integrase strand transfer inhibitors (INSTIs) are the most recent class of antiretroviral drugs to reach the market. INSTIs function by inhibiting the 3’-processing ability of HIV integrase and preventing the incorporation of the HIV genome into the host’s deoxyribonucleic acid (DNA). The use of raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG) in clinical settings has increased since their approval, however there is a risk that the development of drug resistance would impact the treatment of the individual as well as the g…
has type: Thesis/Dissertation
date issued: 2023-05
is shown at: 10.14288/1.0422972
language: eng
degree discipline: Experimental Medicine
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Harrigan, Paul Richard
type: Text
identifier URI: http://hdl.handle.net/2429/83587