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J. Virol. doi:10.1128/JVI.00352-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Selection of T1249-resistant Human Immunodeficiency Virus type 1 variants

Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center of the University of Amsterdam, the Netherlands; Department of Biochemistry, Weill Medical College of Cornell University, New York, United States of America; Pepscan Therapeutics, Lelystad, the Netherlands

^* To whom correspondence should be addressed. Email: b.berkhout{at}amc.uva.nl.

	Abstract

HIV-1 entry is an attractive target for therapeutic intervention. Two drugs that inhibit this process have been approved: the fusion inhibitor T20 (fuzeon, enfuvirtide) 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 starting 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 substitutions 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 substituted for A, G or W) is also responsible for T1249-resistance (substituted for 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 a different resistance mechanism.

This article has been cited by other articles:

• Baldwin, C., Berkhout, B. (2008). Mechanistic Studies of a T20-Dependent Human Immunodeficiency Virus Type 1 Variant. J. Virol. 82: 7735-7740 [Abstract] [Full Text]