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Antimicrobial Agents and Chemotherapy, January 2001, p. 60-66, Vol. 45, No. 1
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.1.60-66.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Role of Human Immunodeficiency Virus (HIV) Type 1 Envelope in the Anti-HIV Activity of the Betulinic Acid Derivative IC9564

Sonia L. Holz-Smith,1 I-Chen Sun,2 Lei Jin,3 Thomas J. Matthews,3 Kuo-Hsiung Lee,2 and Chin Ho Chen1,*

Department of Microbiology, Meharry Medical College, Nashville, Tennessee 37208,1 Natural Products Laboratory, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599,2 and Trimeris Inc., Durham, North Carolina 277103

Received 8 May 2000/Returned for modification 28 July 2000/Accepted 3 October 2000

The betulinic acid derivative IC9564 is a potent anti-human immunodeficiency virus (anti-HIV) compound that can inhibit both HIV primary isolates and laboratory-adapted strains. However, this compound did not affect the replication of simian immunodeficiency virus and respiratory syncytial virus. Results from a syncytium formation assay indicated that IC9564 blocked HIV type 1 (HIV-1) envelope-mediated membrane fusion. Analysis of a chimeric virus derived from exchanging envelope regions between IC9564-sensitive and IC9564-resistant viruses indicated that regions within gp120 and the N-terminal 25 amino acids (fusion domain) of gp41 are key determinants for the drug sensitivity. By developing a drug-resistant mutant from the NL4-3 virus, two mutations were found within the gp120 region and one was found within the gp41 region. The mutations are G237R and R252K in gp120 and R533A in the fusion domain of gp41. The mutations were reintroduced into the NL4-3 envelope and analyzed for their role in IC9564 resistance. Both of the gp120 mutations contributed to the drug sensitivity. On the contrary, the gp41 mutation (R533A) did not appear to affect the IC9564 sensitivity. These results suggest that HIV-1 gp120 plays a key role in the anti-HIV-1 activity of IC9564.

* Corresponding author. Mailing address: Department of Microbiology, Meharry Medical College, 1005 DB. Todd Blvd., Nashville, TN 37208. Phone: (615) 327-6672. Fax: (615) 327-6672. E-mail: cchen{at}mail.mmc.edu.

Antimicrobial Agents and Chemotherapy, January 2001, p. 60-66, Vol. 45, No. 1
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.1.60-66.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Lai, W., Huang, L., Ho, P., Li, Z., Montefiori, D., Chen, C.-H. (2008). Betulinic Acid Derivatives That Target gp120 and Inhibit Multiple Genetic Subtypes of Human Immunodeficiency Virus Type 1. Antimicrob. Agents Chemother. 52: 128-136 [Abstract] [Full Text]  
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  • Huang, L., Yuan, X., Aiken, C., Chen, C. H. (2004). Bifunctional Anti-Human Immunodeficiency Virus Type 1 Small Molecules with Two Novel Mechanisms of Action. Antimicrob. Agents Chemother. 48: 663-665 [Abstract] [Full Text]  
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