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

• Published in: bioRxiv
• Main Authors: Li, Min, Passos, Dario, Zelin Shan, Smith, Steven J, Sun, Qinfang, Biswas, Avik, Choudhuri, Indrani, Strutzenberg, Tim, Haldane, Allan, Deng, Nanjie, Li, Zhaoyang, Xue-Zhi Zhao, Burke, Terrence R, Levy, Ronald M, Hughes, Stephen H, Craigie, Robert, Lyumkis, Dmitry
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 05.12.2022
• Subjects: Chromatin; Drug resistance; Free energy; HIV; Human immunodeficiency virus; Integrase; Patent applications
• DOI: 10.1101/2022.12.04.519057

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 INSTI-resistant 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, 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.Competing Interest StatementCompound 4d is claimed within one or more patent applications