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  IAS 2013: 7th IAS Conference on HIV
Pathogenesis Treatment and Prevention
June 30 - July 3 2013
Kuala Lumpur, Malaysia
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"Evolutionary Dead-End" After Emergence of Primary Dolutegravir Resistance Mutation?
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7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur
Mark Mascolini
Tissue culture studies could identify no secondary resistance mutation that compensates for HIV replication defects seen with the R263K primary dolutegravir resistance mutation [1]. Mark Wainberg and colleagues at Montreal's McGill University proposed that HIV becomes "trapped in an evolutionary dead-end" upon emergence of R263K.
Resistance-conferring mutations have arisen during treatment with all antiretrovirals tested so far, with one exception. Among antiretroviral-naive people starting the investigational integrase inhibitor dolutegravir, researchers have detected no mutations.
To explore possible explanations for lack of clinical resistance to dolutegravir, the McGill team performed classic in vitro selection experiments. They grew HIV-1 in MT-2 cells and peripheral blood mononuclear cells then exposed those cells to increasing concentrations of dolutegravir, starting with 0.05 nM, 4 times less than the 50% effective concentration (EC50) for dolutegravir. After 6 months dolutegravir concentrations reached 50 to 100 nM, and beyond that point HIV-1 could no longer grow.
R263K emerged as the primary resistance mutation in these studies, conferring low-level (2- to 5-fold) resistance to dolutegravir. R263K diminished viral replication about 20% and cut HIV DNA integration into host cells about 20%.
H51Y was the main secondary mutation to arise; E138K or the M50I polymorphism were alternative secondary substitutions. Addition of H51Y to R263K increased resistance to dolutegravir. At the same time, emergence of H51Y further decreased viral replication and HIV DNA integration:
Wild-type virus: No resistance; 100% viral replication; 100% HIV DNA integration R263K: 2- to 5-fold resistance; about 80% viral replication; about 80% HIV DNA integration R263K + H51Y: About 12-fold resistance; about 40% viral replication; about 60% HIV DNA integration
The McGill team saw similar results after emergence of E138K or H50I. Like H51Y, both of these substitutions failed to restore viral replication capacity or mitigate the integration defect caused by R263K.
The researchers noted that, with other antiretrovirals, emergence of secondary mutations typically ratchets up resistance to those drugs while increasing viral replication and enzyme function. They suggested that their findings "may provide an explanation for the absence of de novo resistance mutations against dolutegravir in integrase inhibitor-naive patients." Because none of the secondary mutations observed compensated for R263K-induced defects in viral replication and HIV DNA integration, Wainberg and colleagues suggested "the virus is trapped in an evolutionary dead-end."
The researchers confirmed these findings in site-directed mutagenesis studies [2].
1. Mesplede T, Quashie P, Oliveira M, Wainberg M. HIV resistance to dolutegravir (DTG) simultaneously diminishes viral DNA integration into host cells and viral replication fitness: implications for HIV reservoirs. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur. Abstract MOPE014. http://pag.ias2013.org/EPosterHandler.axd?aid=350
2. Mesplede T, Wares MA, Osman N, et al. Secondary resistance mutations in the R263K integrase inhibitor resistance pathway. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur. Abstract MOPE022. http://pag.ias2013.org/EPosterHandler.axd?aid=1761