JAC Advance Access originally published online on July 1, 2004
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Journal of Antimicrobial Chemotherapy 2004 54(2):333-340; doi:10.1093/jac/dkh330
JAC vol.54 no.2 © The British Society for Antimicrobial Chemotherapy 2004; all rights reserved.
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Resistance to enfuvirtide, the first HIV fusion inhibitor
1 Trimeris Inc., 4727 University Drive, Durham, NC 27707, USA; 2 Roche, Palo Alto, CA, USA
* Corresponding author. Tel: +1-919-419-6050; Email: mgreenberg{at}trimeris.com
Fusion inhibitors are a new class of antiretroviral drugs (ARVs) for the treatment of human immunodeficiency virus infection. Enfuvirtide is the first in this class to reach market approval. Fusion inhibitors block the last step in the three-step viral entry process consisting of attachment, co-receptor binding and fusion, thereby preventing viral capsid entry into the host cell. Enfuvirtide has a unique mechanism of action and high viral target specificity, and in clinical trials has been shown to exhibit both high efficacy and low toxicity. Enfuvirtide is a peptide mimetic of an essential region within viral envelope glycoprotein gp41 that functions by blocking gp41 structural rearrangements at a transitional pre-fusion conformation. Although different clinical isolates show variation in susceptibility to enfuvirtide, primary resistance has not been observed, and thus enfuvirtide-naive isolates remain clinically sensitive. Acquired resistance centres round a 10 amino acid motif between residues 36 and 45 in gp41 that forms part of the binding site of enfuvirtide. The 10 amino acid motif is critical for viral fusion, and enfuvirtide-resistant mutants show poor replicative capacity compared with wild type. Reversion to a wild-type, drug-sensitive state has been reported following enfuvirtide withdrawal.
Keywords: fusion inhibitors , resistance , gp41
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