Mechanisms of HIV-1 integrase resistance to dolutegravir and potent inhibition of drug-resistant variants

Sci Adv. 2023 Jul 21;9(29):eadg5953. doi: 10.1126/sciadv.adg5953. Epub 2023 Jul 21.

Abstract

HIV-1 infection depends on the integration of viral DNA into host chromatin. Integration is mediated by the viral enzyme integrase and is blocked by integrase strand transfer inhibitors (INSTIs), first-line antiretroviral therapeutics widely used in the clinic. Resistance to even the best INSTIs is a problem, and the mechanisms of resistance are poorly understood. Here, we analyze combinations of the mutations E138K, G140A/S, and Q148H/K/R, which confer resistance to INSTIs. The investigational drug 4d more effectively inhibited the mutants compared with the approved drug Dolutegravir (DTG). We present 11 new cryo-EM structures of drug-resistant HIV-1 intasomes bound to DTG or 4d, with better than 3-Å resolution. These structures, complemented with free energy simulations, virology, and enzymology, explain the mechanisms of DTG resistance involving E138K + G140A/S + Q148H/K/R and show why 4d maintains potency better than DTG. These data establish a foundation for further development of INSTIs that potently inhibit resistant forms in integrase.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • HIV Integrase Inhibitors* / chemistry
  • HIV Integrase Inhibitors* / pharmacology
  • HIV Integrase* / chemistry
  • HIV Integrase* / genetics
  • HIV Integrase* / metabolism
  • Mutation
  • Oxazines / pharmacology

Substances

  • HIV Integrase Inhibitors
  • dolutegravir
  • p31 integrase protein, Human immunodeficiency virus 1
  • Oxazines
  • HIV Integrase

Associated data

  • Protein/PDB 8FN7
  • Protein/PDB 8FND
  • Protein/PDB 8FNH
  • Protein/PDB 8FNJ
  • Protein/PDB 8FNL
  • Protein/PDB 8FNM
  • Protein/PDB 8FNP
  • Protein/PDB 8FNQ