G-Quadruplex DNA and Other Non-Canonical B-Form DNA Motifs Influence Productive and Latent HIV-1 Integration and Reactivation Potential
Hannah O. Ajoge,
Hinissan P. Kohio,
Ermela Paparisto,
Macon D. Coleman,
Kemen Wong,
Sean K. Tom,
Katie L. Bain,
Charles C. Berry,
Eric J. Arts,
Stephen D. Barr
Affiliations
Hannah O. Ajoge
Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, Western University, Dental Sciences Building Room 3007, London, ON N6A 5C1, Canada
Hinissan P. Kohio
Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, Western University, Dental Sciences Building Room 3007, London, ON N6A 5C1, Canada
Ermela Paparisto
Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, Western University, Dental Sciences Building Room 3007, London, ON N6A 5C1, Canada
Macon D. Coleman
Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, Western University, Dental Sciences Building Room 3007, London, ON N6A 5C1, Canada
Kemen Wong
Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, Western University, Dental Sciences Building Room 3007, London, ON N6A 5C1, Canada
Sean K. Tom
Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, Western University, Dental Sciences Building Room 3007, London, ON N6A 5C1, Canada
Katie L. Bain
Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, Western University, Dental Sciences Building Room 3007, London, ON N6A 5C1, Canada
Charles C. Berry
Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA 92093, USA
Eric J. Arts
Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, Western University, Dental Sciences Building Room 3007, London, ON N6A 5C1, Canada
Stephen D. Barr
Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, Western University, Dental Sciences Building Room 3007, London, ON N6A 5C1, Canada
The integration of the HIV-1 genome into the host genome is an essential step in the life cycle of the virus and it plays a critical role in the expression, long-term persistence, and reactivation of HIV expression. To better understand the local genomic environment surrounding HIV-1 proviruses, we assessed the influence of non-canonical B-form DNA (non-B DNA) on the HIV-1 integration site selection. We showed that productively and latently infected cells exhibit different integration site biases towards non-B DNA motifs. We identified a correlation between the integration sites of the latent proviruses and non-B DNA features known to potently influence gene expression (e.g., cruciform, guanine-quadruplex (G4), triplex, and Z-DNA). The reactivation potential of latent proviruses with latency reversal agents also correlated with their proximity to specific non-B DNA motifs. The perturbation of G4 structures in vitro using G4 structure-destabilizing or -stabilizing ligands resulted in a significant reduction in integration within 100 base pairs of G4 motifs. The stabilization of G4 structures increased the integration within 300–500 base pairs from G4 motifs, increased integration near transcription start sites, and increased the proportion of latently infected cells. Moreover, we showed that host lens epithelium-derived growth factor (LEDGF)/p75 and cleavage and polyadenylation specificity factor 6 (CPSF6) influenced the distribution of integration sites near several non-B DNA motifs, especially G4 DNA. Our findings identify non-B DNA motifs as important factors that influence productive and latent HIV-1 integration and the reactivation potential of latent proviruses.
