Mechanisms of HIV-1 Integrase Resistance to Dolutegravir and Potent Inhibition of Drug Resistant Variants

Li, M.; Passos, D.; Shan, Z.; Smith, S. J.; Sun, Q.; Biswas, A.; Choudhuri, I.; Strutzenberg, T.; Haldane, A.; Deng, N.; Li, Z.; Zhao, X.-Z.; Burke, T. R.; Levy, R. M.; Hughes, S. H.; Craigie, R.; Lyumkis, D.

doi:10.1101/2022.12.04.519057

bioRxiv · 10.1101/2022.12.04.519057

Mechanisms of HIV-1 Integrase Resistance to Dolutegravir and Potent Inhibition of Drug Resistant Variants

Li, M.·Passos, D.·Shan, Z.·Smith, S. J.·Sun, Q.·Biswas, A.·Choudhuri, I.·Strutzenberg, T.·Haldane, A.·Deng, N.·Li, Z.·Zhao, X.-Z.·Burke, T. R.·Levy, R. M.·Hughes, S. H.·Craigie, R.·Lyumkis, D.

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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 [A] 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.

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Li, M., Passos, D., Shan, Z., Smith, S. J., Sun, Q., Biswas, A., Choudhuri, I., Strutzenberg, T., Haldane, A., Deng, N., Li, Z., Zhao, X.-Z., Burke, T. R., Levy, R. M., Hughes, S. H., Craigie, R., Lyumkis, D.. 2022-12-05. Mechanisms of HIV-1 Integrase Resistance to Dolutegravir and Potent Inhibition of Drug Resistant Variants. https://doi.org/10.1101/2022.12.04.519057

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