Dolutegravir interactions with HIV-1 integrase-DNA: structural rationale for drug resistance and dissociation kinetics

• Published in: PloS one 2013-10, Vol.8 (10), p.e77448
• Main Authors: DeAnda, Felix, Hightower, Kendra E, Nolte, Robert T, Hattori, Kazunari, Yoshinaga, Tomokazu, Kawasuji, Takashi, Underwood, Mark R
• Format: Article
• Language: English
• Subjects: Antiretroviral agents; Antiviral activity; Binding; Catalysis; Cross-resistance; Deoxyribonucleic acid; Dissociation; DNA; Drug interactions; Drug resistance; Drug Resistance, Viral - genetics; Electronic properties; Enzymes; Genetic research; Heterocyclic Compounds, 3-Ring - chemistry; Heterocyclic Compounds, 3-Ring - metabolism; Heterocyclic Compounds, 3-Ring - pharmacology; HIV; HIV Integrase - genetics; HIV Integrase - metabolism; HIV Integrase Inhibitors - chemistry; HIV Integrase Inhibitors - metabolism; HIV Integrase Inhibitors - pharmacology; HIV Long Terminal Repeat - genetics; HIV-1 - drug effects; HIV-1 - genetics; HIV-1 - metabolism; Human immunodeficiency virus; Humans; Infectious diseases; Inhibitors; Integrase; Kinetics; Models, Molecular; Molecular Docking Simulation; Molecular modelling; Molecular Structure; Mutants; Mutation; Nucleic Acid Conformation; Protein Binding; Protein Conformation; Proteins; Proviruses - genetics; Reaction kinetics; Resistance factors; Structural models; Studies; Viruses; Yang, Cindy
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0077448

Signature HIV-1 integrase mutations associated with clinical raltegravir resistance involve 1 of 3 primary genetic pathways, Y143C/R, Q148H/K/R and N155H, the latter 2 of which confer cross-resistance to elvitegravir. In accord with clinical findings, in vitro drug resistance profiling studies with wild-type and site-directed integrase mutant viruses have shown significant fold increases in raltegravir and elvitegravir resistance for the specified viral mutants relative to wild-type HIV-1. Dolutegravir, in contrast, has demonstrated clinical efficacy in subjects failing raltegravir therapy due to integrase mutations at Y143, Q148 or N155, which is consistent with its distinct in vitro resistance profile as dolutegravir's antiviral activity against these viral mutants is equivalent to its activity against wild-type HIV-1. Kinetic studies of inhibitor dissociation from wild-type and mutant integrase-viral DNA complexes have shown that dolutegravir also has a distinct off-rate profile with dissociative half-lives substantially longer than those of raltegravir and elvitegravir, suggesting that dolutegravir's prolonged binding may be an important contributing factor to its distinct resistance profile. To provide a structural rationale for these observations, we constructed several molecular models of wild-type and clinically relevant mutant HIV-1 integrase enzymes in complex with viral DNA and dolutegravir, raltegravir or elvitegravir. Here, we discuss our structural models and the posited effects that the integrase mutations and the structural and electronic properties of the integrase inhibitors may have on the catalytic pocket and inhibitor binding and, consequently, on antiviral potency in vitro and in the clinic.