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

• DOI: 10.1126/sciadv.adg5953
• Publication Date: 2023-07-21T17:58:59Z
• Authors: Min Li; Dario Oliveira Pa...; Zelin Shan; Steven J. Smith; Qinfang Sun; Avik Biswas; Indrani Choudhuri; Timothy S. Strutz...; Allan Haldane; Nanjie Deng; Zhaoyang Li; Xue Zhi Zhao; Lorenzo Briganti; Mamuka Kvaratskhelia; Terrence R. Burke; Ronald M. Levy; Stephen H. Hughes; Robert Craigie; Dmitry Lyumkis
• Keywords: Dolutegravir; Elvitegravir; Integrase inhibitor; Raltegravir

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