Background: In resource-limited countries, integrase strand transfer inhibitors (INSTIs) such as dolutegravir (DTG) are central to antiretroviral therapy (ART). However, the effect of HIV-1 genetic diversity on the efficacy of these new molecules remains underestimated. We modeled interactions between DTG and HIV-1 integrase for 10 subtypes circulating in Cameroon.
Methods: HIV-1 integrase sequences obtained from INSTI-naive patients were generated by Sanger sequencing and edited on RECall v2. 3D structures were then predicted using AlphaFold v3, refined by OpenMM minimization (AMBER14 force field, TIP3P), and validated by the SAVES server (ERRAT, VERIFY3D, PROCHECK). Docking was performed with AutoDock v4.2 and interactions were mapped, considering the DDE triad (D64 – D116 – E152) as the active site . Lowest docking binding energies were selected to identify all amino acids involved in the interaction and their implications.
Results: HIV-1 subtypes modeled were as follows: A3, D, F2, G, H, CRF02_AG, CRF22_01A1, CRF36_cpx, CRF37_cpx, and HIV-1 group N. All successfully passed external structural validation score. Binding energies ranged from -7.29 to -4.88 kcal/mol (Ki: 4.57–275.14 µM), with preservation of the active site and overall fold of the three-dimensional structures in all subtypes (RMSD=0.66 Å)*. Surprisingly, the circulating recombinant forms showed a stronger affinity for Dolutegravir (lowest inhibition constant). Interaction mapping revealed important magnesium ions chelation by dolutegravir during complex formation and several key amino acids that establish hydrogen bonds (C65, H67, K159), halogen bonds (D64, E92, D116), alkyl bonds (I141, P142, K156) and Van der Waals interactions (T66, D116, N155).
Conclusion: This study demonstrates that dolutegravir maintains stable binding across a wide range of HIV-1 integrase forms present in Cameroon. In addition, several amino acids not yet associated with INSTI-resistance were consistently involved in drug binding across highly genetically diverse viruses, suggesting the potential existence of resistance pathways different from those already documented in HIV-1 subtype B.