This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Baba, M.
Right arrow Articles by Takashima, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Baba, M.
Right arrow Articles by Takashima, K.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, February 2007, p. 707-715, Vol. 51, No. 2
0066-4804/07/$08.00+0     doi:10.1128/AAC.01079-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Isolation and Characterization of Human Immunodeficiency Virus Type 1 Resistant to the Small-Molecule CCR5 Antagonist TAK-652{triangledown}

Masanori Baba,1* Hiroshi Miyake,1,2 Xin Wang,1 Mika Okamoto,1 and Katsunori Takashima2

Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544,1 Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Osaka 532-8686, Japan2

Received 27 August 2006/ Returned for modification 20 October 2006/ Accepted 9 November 2006

TAK-652, a novel small-molecule chemokine receptor antagonist, is a highly potent and selective inhibitor of CCR5-using (R5) human immunodeficiency virus type 1 (HIV-1) replication in vitro. Since TAK-652 is orally bioavailable and has favorable pharmacokinetic profiles in humans, it is considered a promising candidate for an entry inhibitor of HIV-1. To investigate the resistance to TAK-652, peripheral blood mononuclear cells were infected with the R5 HIV-1 primary isolate KK and passaged in the presence of escalating concentrations of the compound for more than 1 year. After 67 weeks of cultivation, the escape virus emerged even in the presence of a high concentration of TAK-652. This virus displayed more than 200,000-fold resistance to TAK-652 compared with the wild type. The escape virus appeared to have cross-resistance to the structurally related compound TAK-779 but retained full susceptibility to TAK-220, which is from a different class of CCR5 antagonists. Furthermore, the escape virus was unable to use CXCR4 as a coreceptor. Analysis for Env amino acid sequences of escape viruses at certain points of passage revealed that amino acid changes accumulated with an increasing number of passages. Several amino acid changes not only in the V3 region but also in other Env regions seemed to be required for R5 HIV-1 to acquire complete resistance to TAK-652.

* Corresponding author. Mailing address: Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8544, Japan. Phone: 81 99-275-5930. Fax: 81 99-275-5932. E-mail: m-baba{at}vanilla.ocn.ne.jp.

{triangledown} Published ahead of print on 20 November 2006.

Antimicrobial Agents and Chemotherapy, February 2007, p. 707-715, Vol. 51, No. 2
0066-4804/07/$08.00+0     doi:10.1128/AAC.01079-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Ogert, R. A., Ba, L., Hou, Y., Buontempo, C., Qiu, P., Duca, J., Murgolo, N., Buontempo, P., Ralston, R., Howe, J. A. (2009). Structure-Function Analysis of Human Immunodeficiency Virus Type 1 gp120 Amino Acid Mutations Associated with Resistance to the CCR5 Coreceptor Antagonist Vicriviroc. J. Virol. 83: 12151-12163 [Abstract] [Full Text]  
  • Nolan, K. M., Del Prete, G. Q., Jordan, A. P. O., Haggarty, B., Romano, J., Leslie, G. J., Hoxie, J. A. (2009). Characterization of a Human Immunodeficiency Virus Type 1 V3 Deletion Mutation That Confers Resistance to CCR5 Inhibitors and the Ability To Use Aplaviroc-Bound Receptor. J. Virol. 83: 3798-3809 [Abstract] [Full Text]  
  • Anastassopoulou, C. G., Ketas, T. J., Klasse, P. J., Moore, J. P. (2009). Resistance to CCR5 inhibitors caused by sequence changes in the fusion peptide of HIV-1 gp41. Proc. Natl. Acad. Sci. USA 106: 5318-5323 [Abstract] [Full Text]  
  • Lobritz, M. A., Marozsan, A. J., Troyer, R. M., Arts, E. J. (2007). Natural Variation in the V3 Crown of Human Immunodeficiency Virus Type 1 Affects Replicative Fitness and Entry Inhibitor Sensitivity. J. Virol. 81: 8258-8269 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»