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, resolved to &lt;3 Å. These structures, complemented with Potts model analysis and molecular dynamics based free energy simulations, explain the mechanisms of DTG resistance involving E138K+G140A/S+Q148H/K/R and show why 4d maintains potency better than DTG. These data highlight how experimental and computational tools provide synergistic insights useful for defining mechanisms of resistance to current therapies and establish a foundation for further development of INSTIs that potently inhibit resistant forms in integrase.

Mechanisms of resistance to integrase strand transfer inhibitors and potent inhibition of drug-resistant variants

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