Cell studies predict cross-resistance among integrase inhibitors

Mark Mascolini,

Serial passage studies involving the Japan Tobacco/Gilead integrase inhibitor GS-9137 identified several resistance-conferring mutations, one of which can render HIV resistant to the drug by itself [1]. The study also yielded evidence of cross-resistance between GS-9137 and two other integrase inhibitors no longer being developed.

Researchers from Japan Tobacco and Kyoto’s Institute for Virus Research performed classic serial passage studies in which technicians propagated lab strains of HIV while subjecting cultures to slowly increasing doses of an antiretroviral. This exercise revealed an E92Q mutation in the integrase catalytic core domain after 30 passages. H51Y and S147G joined E92Q after 60 passages. E157Q arose during passage 70.

Studies testing the susceptibility of HIV-1 to GS-9137, to the earlier Merck integrase inhibitor candidate L-870,810 [2], and to AZT indicated that E92Q alone confers resistance to GS-9137 and cross-resistance to L-870,810. Susceptibility to both GS-9137 and L-870,810 dropped dramatically when the researchers engineered molecular clones to carry two or three of the identified mutations. Clusters of different mutations identified earlier in studies of two Merck integrase inhibitor candidates also rendered virus highly resistant to GS-9137.

The researchers also presented data showing that virus isolated from 4 people with antiretroviral experience remains highly susceptible to GS-9137, as one would expect.


  1. Kodama E, Shimura K, Sakagami Y, et al. In vitro antiviral activity and resistance profile of a novel HIV integrase inhibitor JTK-303/GS-9137. 46th ICAAC. September 27-30, 2006, San Francisco. Abstract H-254.
  2. Little S, Drusano G, Schooley R, et al. Antiretroviral effect of L-000870810, a novel HIV-1 integrase inhibitor, in HIV-1-infected patients. 12th Conference on Retroviruses and Opportunistic Infections. February 22-25, 2005. Boston. Abstract 161.

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