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Antimicrobial Agents and Chemotherapy, February 2006, p. 547-555, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.547-555.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Inhibition of Human Immunodeficiency Virus Type 1 Replication in Latently Infected Cells by a Novel I{kappa}B Kinase Inhibitor

Ann Florence B. Victoriano,1 Kaori Asamitsu,1 Yurina Hibi,1 Kenichi Imai,1 Nina G. Barzaga,2 and Takashi Okamoto1*

Department of Molecular and Cellular Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan,1 Department of Medical Microbiology, College of Public Health, University of the Philippines, Manila, Philippines2

Received 16 July 2005/ Returned for modification 22 September 2005/ Accepted 4 November 2005

In human immunodeficiency virus type 1 (HIV-1) latently infected cells, NF-{kappa}B plays a major role in the transcriptional induction of HIV-1 replication. Hence, downregulation of NF-{kappa}B activation has long been sought for effective anti-HIV therapy. Tumor necrosis factor alpha (TNF-{alpha}) stimulates I{kappa}B kinase (IKK) complex, a critical regulator in the NF-{kappa}B signaling pathway. A novel IKK inhibitor, ACHP {2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl-nicotinonitrile}, was developed and evaluated as a potent and specific inhibitor for IKK-{alpha} and IKK-ß. In this study, we examined the ability of this compound to inhibit HIV-1 replication in OM10.1 cells latently infected with HIV. When these cells were pretreated with ACHP, TNF-{alpha}-induced HIV-1 replication was dramatically inhibited, as measured by the HIV p24 antigen levels in the culture supernatants. Its 50% effective concentration was approximately 0.56 µM, whereas its 50% cytotoxic concentration was about 15 µM. Western blot analysis revealed inhibition of I{kappa}B{alpha} phosphorylation, I{kappa}B{alpha} degradation, p65 nuclear translocation, and p65 phosphorylation. ACHP was also found to suppress HIV-1 long terminal repeat (LTR)-driven gene expression through the inhibition of NF-{kappa}B activation. Furthermore, ACHP inhibited TNF-{alpha}-induced NF-{kappa}B (p65) recruitment to the HIV-1 LTR, as assessed by chromatin immunoprecipitation assay. These findings suggest that ACHP acts as a potent suppressor of TNF-{alpha}-induced HIV replication in latently infected cells and that this inhibition is mediated through suppression of IKK activity.

* Corresponding author. Mailing address: Department of Molecular and Cellular Biology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan. Phone: 81-52-853-8204. Fax: 81-52-859-1235. E-mail: tokamoto{at}med.nagoya-cu.ac.jp.

Antimicrobial Agents and Chemotherapy, February 2006, p. 547-555, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.547-555.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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  • Asamitsu, K., Yamaguchi, T., Nakata, K., Hibi, Y., Victoriano, A.-F. B., Imai, K., Onozaki, K., Kitade, Y., Okamoto, T. (2008). Inhibition of Human Immunodeficiency Virus Type 1 Replication by Blocking I{kappa}B Kinase with Noraristeromycin. J Biochem 144: 581-589 [Abstract] [Full Text]  
  • Gao, N., Asamitsu, K., Hibi, Y., Ueno, T., Okamoto, T. (2008). AKIP1 Enhances NF-{kappa}B-dependent Gene Expression by Promoting the Nuclear Retention and Phosphorylation of p65. J. Biol. Chem. 283: 7834-7843 [Abstract] [Full Text]  


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