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Journal of Virology, October 2005, p. 12773-12782, Vol. 79, No. 20
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.20.12773-12782.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

TMC125 Displays a High Genetic Barrier to the Development of Resistance: Evidence from In Vitro Selection Experiments

Johan Vingerhoets,1 Hilde Azijn,1 Els Fransen,1 Inky De Baere,1 Liesbet Smeulders,1 Dirk Jochmans,1 Koen Andries,2 Rudi Pauwels,1,{dagger} and Marie-Pierre de Béthune1*

Tibotec, Mechelen, Belgium,1 and Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium2

Received 4 May 2005/ Accepted 22 July 2005

TMC125 is a potent new investigational nonnucleoside reverse transcriptase inhibitor (NNRTI) that is active against human immunodeficiency virus type 1 (HIV-1) with resistance to currently licensed NNRTIs. Sequential passage experiments with both wild-type virus and NNRTI-resistant virus were performed to identify mutations selected by TMC125 in vitro. In addition to "classic" selection experiments at a low multiplicity of infection (MOI) with increasing concentrations of inhibitors, experiments at a high MOI with fixed concentrations of inhibitors were performed to ensure a standardized comparison between TMC125 and current NNRTIs. Both low- and high-MOI experiments demonstrated that the development of resistance to TMC125 required multiple mutations which frequently conferred cross-resistance to efavirenz and nevirapine. In high-MOI experiments, 1 µM TMC125 completely inhibited the breakthrough of resistant virus from wild-type and NNRTI-resistant HIV-1, in contrast to efavirenz and nevirapine. Furthermore, breakthrough of virus from site-directed mutant (SDM) SDM-K103N/Y181C occurred at the same time or later with TMC125 as breakthrough from wild-type HIV-1 with efavirenz or nevirapine. The selection experiments identified mutations selected by TMC125 that included known NNRTI-associated mutations L100I, Y181C, G190E, M230L, and Y318F and the novel mutations V179I and V179F. Testing the antiviral activity of TMC125 against a panel of SDMs indicated that the impact of these individual mutations on resistance was highly dependent upon the presence and identity of coexisting mutations. These results demonstrate that TMC125 has a unique profile of activity against NNRTI-resistant virus and possesses a high genetic barrier to the development of resistance in vitro.

* Corresponding author. Mailing address: Tibotec BVBA, Gen de Wittelaan L 11B 3, Mechelen 2800, Belgium. Phone: 32 15 401 240. Fax: 32 15 444 290. E-mail: mdbethun{at}tibbe.jnj.com.

{dagger} Present address: Johnson & Johnson Pharmaceutical Research & Development, St-Légier, Switzerland.

Journal of Virology, October 2005, p. 12773-12782, Vol. 79, No. 20
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.20.12773-12782.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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