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Journal of Virology, November 2004, p. 12428-12437, Vol. 78, No. 22
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.22.12428-12437.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Emergence of a Drug-Dependent Human Immunodeficiency Virus Type 1 Variant during Therapy with the T20 Fusion Inhibitor

Chris E. Baldwin,1 Rogier W. Sanders,1 Yiqun Deng,2 Suzanne Jurriaans,1 Joep M. Lange,3 Min Lu,2 and Ben Berkhout1*

Department of Human Retrovirology,1 National AIDS Therapy Evaluation Center, Academic Medical Center, University of Amsterdam, The Netherlands,2 Department of Biochemistry, Weill Medical College of Cornell University, New York, New York3

Received 19 March 2004/ Accepted 4 June 2004

The fusion inhibitor T20 belongs to a new class of anti-human immunodeficiency virus type 1 (HIV-1) drugs designed to block entry of the virus into the host cell. However, the success of T20 has met with the inevitable emergence of drug-resistant HIV-1 variants. We describe an evolutionary pathway taken by HIV-1 to escape from the selective pressure of T20 in a treated patient. Besides the appearance of T20-resistant variants, we report for the first time the emergence of drug-dependent viruses with mutations in both the HR1 and HR2 domains of envelope glycoprotein 41. We propose a mechanistic model for the dependence of HIV-1 entry on the T20 peptide. The T20-dependent mutant is more prone to undergo the conformational switch that results in the formation of the fusogenic six-helix bundle structure in gp41. A premature switch will generate nonfunctional envelope glycoproteins (dead spikes) on the surface of the virion, and T20 prevents this abortive event by acting as a safety pin that preserves an earlier prefusion conformation.

* Corresponding author. Mailing address: Department of Human Retrovirology, Academic Medical Center, 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.

Journal of Virology, November 2004, p. 12428-12437, Vol. 78, No. 22
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.22.12428-12437.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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