Identification of novel mutations responsible for resistance to MK-2048, a second-generation HIV-1 integrase inhibitor

Tamara Bar-Magen, Richard D. Sloan, Daniel A. Donahue, Björn D. Kuhl, Alexandra Zabeida, Hongtao Xu, Maureen Oliveira, Daria J. Hazuda, Mark A. Wainberg

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

MK-2048 represents a prototype second-generation integrase strand transfer inhibitor (INSTI) developed with the goal of retaining activity against viruses containing mutations associated with resistance to first-generation INSTIs, raltegravir (RAL) and elvitegravir (EVG). Here, we report the identification of mutations (G118R and E138K) which confer resistance to MK-2048 and not to RAL or EVG. These mutations were selected in vitro and confirmed by site-specific mutagenesis. G118R, which appeared first in cell culture, conferred low levels of resistance to MK-2048. G118R also reduced viral replication capacity to approximately 1% that of the isogenic wild-type (wt) virus. The subsequent selection of E138K partially restored replication capacity to ≈13% of wt levels and increased resistance to MK-2048 to ≈8-fold. Viruses containing G118R and E138K remained largely susceptible to both RAL and EVG, suggesting a unique interaction between this second-generation INSTI and the enzyme may be defined by these residues as a potential basis for the increased intrinsic affinity and longer "off" rate of MK-2048. In silico structural analysis suggests that the introduction of a positively charged arginine at position 118, near the catalytic amino acid 116, might decrease Mg2+ binding, compromising enzyme function and thus leading to the significant reduction in both integration and viral replication capacity observed with these mutations.

Original languageEnglish
Pages (from-to)9210-9216
Number of pages7
JournalJournal of Virology
Volume84
Issue number18
DOIs
Publication statusPublished - 15 Sept 2010

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