Session Speaker

HIV-1 Integrase Inhibitors: Role of Natural Diversity on Drug Efficacy and Resistance
Leondios Kostrikis , Eriketi Loizidou
Cyprus

Background: Integrase inhibitors represent the latest addition to the treatment of HIV-1 but their resistance patterns and efficacy among the HIV-1 inter-subtypes remain elusive. This study aims to analyze the binding parameters of integrase inhibitors with respect to efficacy and resistance development.

Materials & Methods: The methodology involved a combination of computational and genetic analyses. Integrase sequences within M group strains from 108 HIV-1 infected patients were analyzed and the polymorphic residues were compared to the residues associated with catalytic activity and drug resistance. Computational structural analysis involved docking of 50 integrase inhibitors in preclinical development, including the most advanced Raltegravir and Elvitegravir.

Results: The residues associated with catalytic activity and primary drug resistance were conserved in all subtypes. The residues involved with primary resistance to Raltegravir Y143, Q148 and N155 were identified in the interacting residues between integrase and Raltegravir. The genetic analysis identified the non-conservative mutations G118R and G140R in a single subtype C strain. Docking of Raltegravir at the active site of the particular subtype C strain identified an alternative list of interacting residues between integrase and Raltegravir. Differences were also observed in the energetic binding parameters among the different classes of integrase inhibitors that correlated with drug resistance patterns. Quantitative-Property-Activity-Relationships correlated experimental IC50 values to the binding energy and the logarithm of the partition coefficient between n-octanol and water (clogP).

Conclusions: A two-way binding mode of Raltegravir within subtype B strains may offer an explanation of the different resistance pathways, the Q148 or N155 and Y143. Furthermore, the pre-existence of non-conservative substitutions in amino acids that are critical for integrase activity and involved in drug resistance may affect the binding mode of Raltegravir. The approach followed here serves as an improved basis for the development of "second generation" integrase inhibitors.