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J Antimicrob Chemother. 2014 Oct;69(10):2733-40. doi: 10.1093/jac/dku199. Epub 2014 Jun 10.

Addition of E138K to R263K in HIV integrase increases resistance to dolutegravir, but fails to restore activity of the HIV integrase enzyme and viral replication capacity.

Author information

1
McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Québec, Canada.
2
McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Québec, Canada Department of Microbiology and Immunology, Faculty of Medicine, McGill University, Montréal, Québec, Canada.
3
McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Québec, Canada Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, Québec, Canada.
4
McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Québec, Canada Department of Microbiology and Immunology, Faculty of Medicine, McGill University, Montréal, Québec, Canada Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, Québec, Canada mark.wainberg@mcgill.ca.

Abstract

BACKGROUND:

The results of several clinical trials suggest that the integrase inhibitor dolutegravir may be less prone than other drugs to the emergence of HIV drug resistance mutations in treatment-naive patients. We have shown that the R263K mutation commonly emerged during tissue culture selection studies with dolutegravir and conferred low levels of resistance to this drug while simultaneously diminishing both HIV replication capacity and integrase enzymatic activity. E138K has been identified as a secondary mutation for dolutegravir in selection studies and has also been observed as a secondary mutation in the clinic for the integrase inhibitors raltegravir and elvitegravir.

METHODS:

We used biochemical cell-free strand-transfer assays and tissue culture assays to characterize the effects of the E138K/R263K combination of mutations on resistance to dolutegravir, integrase enzyme activity and HIV-1 replication capacity.

RESULTS:

We show here that the addition of the E138K substitution to R263K increased the resistance of HIV-1 to dolutegravir but failed to restore viral replication capacity, integrase strand-transfer activity and integration within cellular DNA. We also show that the addition of E138K to R263K did not increase the resistance to raltegravir or elvitegravir. The addition of the E138K substitution to R263K was also less detrimental to integrase strand-transfer activity and integration than a different secondary mutation at position H51Y that had also been selected in culture.

CONCLUSIONS:

The E138K substitution failed to restore the defect in viral replication capacity that is associated with R263K, confirming previous selection studies that failed to identify compensatory mutation(s) for the latter primary mutation. This study suggests that the R263K resistance pathway may represent an evolutionary dead end for HIV in treatment-naive individuals who are treated with dolutegravir and will need to be confirmed by the long-term use of dolutegravir in the clinic.

KEYWORDS:

HIV-1; antiviral; integrase inhibitors

PMID:
24917583
PMCID:
PMC4164141
DOI:
10.1093/jac/dku199
[Indexed for MEDLINE]
Free PMC Article
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