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Journal of Virology, July 2008, p. 6678-6688, Vol. 82, No. 13
0022-538X/08/$08.00+0     doi:10.1128/JVI.00352-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Selection of T1249-Resistant Human Immunodeficiency Virus Type 1 Variants{triangledown}

Dirk Eggink,1 Christopher E. Baldwin,1 Yiqun Deng,2 Johannes P. M. Langedijk,3 Min Lu,2 Rogier W. Sanders,1 and Ben Berkhout1*

Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam, Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands,1 Department of Biochemistry, Weill Medical College of Cornell University, New York, New York,2 Pepscan Therapeutics, Lelystad, The Netherlands3

Received 18 February 2008/ Accepted 16 April 2008

Human immunodeficiency virus type 1 (HIV-1) entry is an attractive target for therapeutic intervention. Two drugs that inhibit this process have been approved: the fusion inhibitor T20 (enfuvirtide [Fuzeon]) and, more recently, the CCR5 blocker maraviroc (Selzentry). T1249 is a second-generation fusion inhibitor with improved antiviral potency compared to the first-generation peptide T20. We selected T1249-resistant HIV-1 variants in vitro by serial virus passage in the presence of increasing T1249 doses after passage with wild-type and T20-resistant variants. Sequence analysis revealed the acquisition of substitutions within the HR1 region of the gp41 ectodomain. The virus acquired mutations of residue V38 to either E or R in 10 of 19 cultures. Both E and R at position 38 were confirmed to cause resistance to T1249, as well as cross-resistance to T20 and C34, but not to the third-generation fusion inhibitor T2635. We also observed substitutions at residues 79 and 90 (Q79E and K90E), which provide modest resistance to T1249 and, interestingly, T2635. Thus, the gp41 amino acid position implicated in T20 resistance (V38 replaced by A, G, or W) is also responsible for T1249 resistance (V38 replaced by E, R, or K). These results indicate that T20 and T1249 exhibit very similar inhibition modes that call for similar but not identical resistance mutations. All T1249-resistant viruses with changes at position 38 are cross resistant to T20, but not vice versa. Furthermore, substitutions at position 38 do not provide resistance to the third-generation inhibitor T2635, while substitution at positions 79 and 90 do, suggesting different resistance mechanisms.

* Corresponding author. Mailing address: Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center of the University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. Phone: 31-20-5664822. Fax: 31-20-6916531. E-mail: b.berkhout{at}amc.uva.nl

{triangledown} Published ahead of print on 23 April 2008.

Journal of Virology, July 2008, p. 6678-6688, Vol. 82, No. 13
0022-538X/08/$08.00+0     doi:10.1128/JVI.00352-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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