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The HIV-1 RT Mutant Q151L Shows Decreased
Replication Capacity, Selective High-Level
Resistance to GS-9148 and Hypersusceptibility
to Tenofovir and Zidovudine
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XVIII International HIV Drug Resistance Workshop
June 9-13, 2009
Fort Myers, Florida
Rima Kulkarni, Nicolas Margot, Florence Myrick, Jenny Svarovskaia, James
Chen, Eric Lansdon, Adrian Ray, Tomas Cihlar, S Swaminathan, Michael Miller,
and Kirsten White
Gilead Sciences, Inc., Foster City, CA, and Durham, NC, USA
"The investigational nucleotide reverse transcriptase inhibitor (NRTI) GS-9148 (GS-9131 is prodrug) maintains potent activity against a majority of clinically observed resistance mutations". "The hyperssusceptibility of Q151L to tenofovir and AZT suggest potential utility of combination therapy of GS-9131 with these agents". From Jules: it appears the drug is potentially active against tenofovir resistance, is more potent than tenofovir, has less if any renal side effects, and tenofovir might be active against GS-9148 resistance. This drug has potential use for patients. Gilead has placed development of this drug on hold.
AUTHOR CONCLUSIONS
![mutation-1.gif](../images/061009/mutation-1.gif)
![produg-2.gif](../images/061009/produg-2.gif)
Introduction
GS-9148 (Fig. 1) is a novel nucleotide HIV RT inhibitor (NtRTI) that
maintains potent activity against a majority of clinically observed
resistance mutations including M184V, K65R, L74V, and ≥ 4 TAMs1
GS-9148 has low-level cross-resistance to Q151M + complex
GS-9131 (Fig. 1), an orally bioavailable phosphonoamidate prodrug
of GS-9148, was designed to effi ciently enter PBMCs in vivo and then
release GS-9148 intracellularly2
GS-9131 has completed initial phase I evaluation in HIV-1 infected
patients
A GS-9148 resistance selection with HIV-1 IIIB previously resulted in
K70E+D123N+T165I RT mutations and low-level reduced susceptibility
to GS-91487
OBJECTIVES
To further characterize the resistance that develops to GS-9148 in vitro
To evaluate the cross-resistance of the selected mutations to other
N(t)RTIs
To characterize the developing resistance mutations for their impact
on viral replication capacity
![Lai-3.gif](../images/061009/Lai-3.gif)
![vitrio-4.gif](../images/061009/vitrio-4.gif)
![ASSAY-5.gif](../images/061009/ASSAY-5.gif)
![fold-6.gif](../images/061009/fold-6.gif)
![NRTI-7.gif](../images/061009/NRTI-7.gif)
![table3-8.gif](../images/061009/table3-8.gif)
![defect-9.gif](../images/061009/defect-9.gif)
![moitey-10.gif](../images/061009/moitey-10.gif)
![suscept-11.gif](../images/061009/suscept-11.gif)
References
1. Cihlar, et al., Antimicrobial Agents and Chemotherapy (2008) 52(2):655-665.
2. Ray, et al., Antimicrobial Agents and Chemotherapy (2008) 52(2):648-654.
3. Petropoulos, et al., Antimicrobial Agents and Chemotherapy (2000) 44(4):920-928.
4. Lansdon, et al., CROI (2009) Abstract # 66LB.
5. Huang, et al., Science (1998) 282:1669-1675.
6. Stanford HIV database: http://hivdb.stanford.edu/index.html. Database accessed on May 1, 2009.
7. Lafl amme, et al., ICAAC (2007) Poster # H-1037.
8. Kosalaraksa, et al., Journal of Virology (1999) 73(7): 5356-5663.
We would like to thank Eric Lam and Monogram Biosciences for their contributions. We would also like to thank
Bob Shafer and the Stanford HIV Database.
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