Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Master of Science

Program

Microbiology and Immunology

Supervisor

Stephen Barr

Abstract

Human immunodeficiency virus type 1 (HIV-1) establishes lifelong infection by integrating its genome into host DNA. While integrase strand transfer inhibitors (INSTIs) effectively block new integration events, therapeutic- and immune-mediated clearance are limited by two challenges: the emergence of drug-resistant variants and the persistence of latent reservoirs. As integration underlies both INSTI resistance and latency, this thesis uses a bioinformatics approach to investigate factors shaping HIV-1 integration site dynamics. Under prolonged drug exposure, we showed that proviral landscapes shift towards genomic regions that support long-term persistence, driven in part by drug-resistant variants harbouring major mutations (e.g., R263K in HIV-1 integrase). We also identified host proteins (e.g., nucleophosmin) that interact with HIV-1 pre-integration complexes, some of which direct integration toward G-quadruplex-rich regions—structures linked to both latent and reactivated proviral states. Altogether, our work offers key insights into how integration shapes drug resistance and latency, guiding future strategies against persistent infections.

Summary for Lay Audience

Since its discovery in the early 1980s, human immunodeficiency virus type 1 (HIV-1) has remained at the forefront of one of the most persistent global health crises. As the causative agent of acquired immunodeficiency syndrome (AIDS), HIV-1 progressively weakens the immune system, leaving individuals highly susceptible to life-threatening infections and malignancies. As a retrovirus, HIV-1 can hijack the host’s cellular machinery to replicate and integrates its genetic material into the host genome, forming a provirus. This integration step is a defining moment in infection, establishing a permanent viral presence that current treatments cannot remove.

To manage the virus, antiretroviral therapies, particularly integrase strand transfer inhibitors (INSTIs), have been developed to suppress replication and block integration into healthy cells. However, two major obstacles remain: drug resistance and viral latency. HIV-1’s high mutation rate gives rise to drug-resistant variants that can compromise treatment effectiveness. At the same time, the virus can enter a latent state, producing little to no viral products and effectively evading immune detection and drug activity. Latent reservoirs, seeded during integration, can persist silently for years, and reignite infection if therapy is interrupted. Together, drug resistance and latency reinforce each other, posing major barriers to long-term control and cure.

Given that integration is central to both lifelong infection and the establishment of latency, it represents a critical target for intervention. This thesis explores the genomic and proteomic factors that influence HIV-1 integration. We showed that the proviral landscape evolves under prolonged drug pressure, favouring genomic regions that support long-term infection. We also demonstrated how integration site selection is altered by drug-resistant variants, highlighting specific mutations commonly found in people living with HIV-1 and those on INSTI regimens. In addition, we characterized host-virus interactions that guide integration, focusing on host factors, such as nucleolin and nucleophosmin, that influence both the efficiency and specificity of this process across different biological contexts. Overall, by deepening our understanding of integration and the proviral landscape, this work aims to uncover new strategies to prevent drug resistance, disrupt latency, and move closer to achieving lasting control, or even a cure, for HIV-1.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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Available for download on Friday, June 18, 2027

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