The Evolving HIV-1 Proviral Landscape: Integration Site Dynamics and Biases Under Drug Resistance and Viral Latency

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.