JAC Advance Access originally published online on July 1, 2004
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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.
Review |
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
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Fransen, S. Gupta, R. Danovich, D. Hazuda, M. Miller, M. Witmer, C. J. Petropoulos, and W. Huang Loss of Raltegravir Susceptibility by Human Immunodeficiency Virus Type 1 Is Conferred via Multiple Nonoverlapping Genetic Pathways J. Virol., November 15, 2009; 83(22): 11440 - 11446. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Eggink, J. P. M. Langedijk, A. M. J. J. Bonvin, Y. Deng, M. Lu, B. Berkhout, and R. W. Sanders Detailed Mechanistic Insights into HIV-1 Sensitivity to Three Generations of Fusion Inhibitors J. Biol. Chem., September 25, 2009; 284(39): 26941 - 26950. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Pan, L. Cai, H. Lu, Z. Qi, and S. Jiang Combinations of the First and Next Generations of Human Immunodeficiency Virus (HIV) Fusion Inhibitors Exhibit a Highly Potent Synergistic Effect against Enfuvirtide- Sensitive and -Resistant HIV Type 1 Strains J. Virol., August 15, 2009; 83(16): 7862 - 7872. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. G. Hermann, L. Egerer, F. Brauer, C. Gerum, H. Schwalbe, U. Dietrich, and D. von Laer Mutations in gp120 Contribute to the Resistance of Human Immunodeficiency Virus Type 1 to Membrane-Anchored C-Peptide maC46 J. Virol., May 15, 2009; 83(10): 4844 - 4853. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ray, L. A. Blackburn, and R. W. Doms HR-2 Mutations in Human Immunodeficiency Virus Type 1 gp41 Restore Fusion Kinetics Delayed by HR-1 Mutations That Cause Clinical Resistance to Enfuvirtide J. Virol., April 1, 2009; 83(7): 2989 - 2995. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Stoddart, G. Nault, S. A. Galkina, K. Thibaudeau, P. Bakis, N. Bousquet-Gagnon, M. Robitaille, M. Bellomo, V. Paradis, P. Liscourt, et al. Albumin-conjugated C34 Peptide HIV-1 Fusion Inhibitor: EQUIPOTENT TO C34 AND T-20 IN VITRO WITH SUSTAINED ACTIVITY IN SCID-HU THY/LIV MICE J. Biol. Chem., December 5, 2008; 283(49): 34045 - 34052. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. He, J. Cheng, H. Lu, J. Li, J. Hu, Z. Qi, Z. Liu, S. Jiang, and Q. Dai Potent HIV fusion inhibitors against Enfuvirtide-resistant HIV-1 strains PNAS, October 21, 2008; 105(42): 16332 - 16337. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Huang, J. Toma, S. Fransen, E. Stawiski, J. D. Reeves, J. M. Whitcomb, N. Parkin, and C. J. Petropoulos Coreceptor Tropism Can Be Influenced by Amino Acid Substitutions in the gp41 Transmembrane Subunit of Human Immunodeficiency Virus Type 1 Envelope Protein J. Virol., June 1, 2008; 82(11): 5584 - 5593. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Cheng, A. Montero, P. Gastaminza, C. Whitten-Bauer, S. F. Wieland, M. Isogawa, B. Fredericksen, S. Selvarajah, P. A. Gallay, M. R. Ghadiri, et al. A virocidal amphipathic {alpha}-helical peptide that inhibits hepatitis C virus infection in vitro PNAS, February 26, 2008; 105(8): 3088 - 3093. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Chinnadurai, D. Rajan, J. Munch, and F. Kirchhoff Human Immunodeficiency Virus Type 1 Variants Resistant to First- and Second-Version Fusion Inhibitors and Cytopathic in Ex Vivo Human Lymphoid Tissue J. Virol., June 15, 2007; 81(12): 6563 - 6572. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ray, J. E. Harrison, L. A. Blackburn, J. N. Martin, S. G. Deeks, and R. W. Doms Clinical Resistance to Enfuvirtide Does Not Affect Susceptibility of Human Immunodeficiency Virus Type 1 to Other Classes of Entry Inhibitors J. Virol., April 1, 2007; 81(7): 3240 - 3250. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Amberg, R. C. Netter, G. Simmons, and P. Bates Expanded Tropism and Altered Activation of a Retroviral Glycoprotein Resistant to an Entry Inhibitor Peptide J. Virol., January 1, 2006; 80(1): 353 - 359. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Strizki, C. Tremblay, S. Xu, L. Wojcik, N. Wagner, W. Gonsiorek, R. W. Hipkin, C.-C. Chou, C. Pugliese-Sivo, Y. Xiao, et al. Discovery and Characterization of Vicriviroc (SCH 417690), a CCR5 Antagonist with Potent Activity against Human Immunodeficiency Virus Type 1 Antimicrob. Agents Chemother., December 1, 2005; 49(12): 4911 - 4919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Winters and T. C. Merigan Insertions in the Human Immunodeficiency Virus Type 1 Protease and Reverse Transcriptase Genes: Clinical Impact and Molecular Mechanisms Antimicrob. Agents Chemother., July 1, 2005; 49(7): 2575 - 2582. [Full Text] [PDF]
|
|
|
|
|
|
T. R. Suntoke and D. C. Chan The Fusion Activity of HIV-1 gp41 Depends on Interhelical Interactions J. Biol. Chem., May 20, 2005; 280(20): 19852 - 19857. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kinomoto, M. Yokoyama, H. Sato, A. Kojima, T. Kurata, K. Ikuta, T. Sata, and K. Tokunaga Amino Acid 36 in the Human Immunodeficiency Virus Type 1 gp41 Ectodomain Controls Fusogenic Activity: Implications for the Molecular Mechanism of Viral Escape from a Fusion Inhibitor J. Virol., May 15, 2005; 79(10): 5996 - 6004. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Reeves, F.-H. Lee, J. L. Miamidian, C. B. Jabara, M. M. Juntilla, and R. W. Doms Enfuvirtide Resistance Mutations: Impact on Human Immunodeficiency Virus Envelope Function, Entry Inhibitor Sensitivity, and Virus Neutralization J. Virol., April 15, 2005; 79(8): 4991 - 4999. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Liu, H. Lu, J. Niu, Y. Xu, S. Wu, and S. Jiang Different from the HIV Fusion Inhibitor C34, the Anti-HIV Drug Fuzeon (T-20) Inhibits HIV-1 Entry by Targeting Multiple Sites in gp41 and gp120 J. Biol. Chem., March 25, 2005; 280(12): 11259 - 11273. [Abstract] [Full Text] [PDF]
|
|