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Zhang, Wendy W.

University of British Columbia

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 INSTI resistance using a phenotypic assay in order to populate a database of matched genotype-phenotype data. High levels of resistance to the new INSTIs, BIC and CAB, were detected and BIC and CAB resistance was found to be highly correlated with DTG resistance, highlighting the similarity between the new and current INSTIs.

Text

2023-01-05

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/83587

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/