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Journal of Virology, November 2006, p. 10957-10971, Vol. 80, No. 22
0022-538X/06/$08.00+0     doi:10.1128/JVI.01369-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

In Vitro Resistance to the Human Immunodeficiency Virus Type 1 Maturation Inhibitor PA-457 (Bevirimat){triangledown}

Catherine S. Adamson,1 Sherimay D. Ablan,1 Ioana Boeras,2 Ritu Goila-Gaur,1 Ferri Soheilian,3 Kunio Nagashima,3 Feng Li,4 Karl Salzwedel,4 Michael Sakalian,2 Carl T. Wild,4 and Eric O. Freed1*

Virus-Cell Interaction Section, HIV Drug Resistance Program, National Cancer Institute, Frederick, Maryland 21702-1201,1 Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104,2 Image Analysis Laboratory, Research Technology Program, SAIC-Frederick, National Cancer Institute at Frederick, Frederick, Maryland 21702-1201,3 Panacos Pharmaceuticals Inc., 209 Perry Parkway, Gaithersburg, Maryland 208774

Received 28 June 2006/ Accepted 21 August 2006

3-O-(3',3'-dimethylsuccinyl)betulinic acid (PA-457 or bevirimat) potently inhibits human immunodeficiency virus type 1 (HIV-1) maturation by blocking a late step in the Gag processing pathway, specifically the cleavage of SP1 from the C terminus of capsid (CA). To gain insights into the mechanism(s) by which HIV-1 could evolve resistance to PA-457 and to evaluate the likelihood of such resistance arising in PA-457-treated patients, we sought to identify and characterize a broad spectrum of HIV-1 variants capable of conferring resistance to this compound. Numerous independent rounds of selection repeatedly identified six single-amino-acid substitutions that independently confer PA-457 resistance: three at or near the C terminus of CA (CA-H226Y, -L231F, and -L231M) and three at the first and third residues of SP1 (SP1-A1V, -A3T, and -A3V). We determined that mutations CA-H226Y, CA-L231F, CA-L231M, and SP1-A1V do not impose a significant replication defect on HIV-1 in culture. In contrast, mutations SP1-A3V and -A3T severely impaired virus replication and inhibited virion core condensation. The replication defect imposed by SP1-A3V was reversed by a second-site compensatory mutation in CA (CA-G225S). Intriguingly, high concentrations of PA-457 enhanced the maturation of SP1 residue 3 mutants. The different phenotypes associated with mutations that confer PA-457 resistance suggest the existence of multiple mechanisms by which HIV-1 can evolve resistance to this maturation inhibitor. These findings have implications for the ongoing development of PA-457 to treat HIV-1 infection in vivo.

* Corresponding author. Mailing address: Virus-Cell Interaction Section, HIV Drug Resistance Program, NCI-Frederick, Bldg. 535/Rm. 108, 1050 Boyles Street, Frederick, MD 21702-1201. Phone: (301) 846-6223. Fax: (301) 846-6777. E-mail: efreed{at}nih.gov.

{triangledown} Published ahead of print on 6 September 2006.

Journal of Virology, November 2006, p. 10957-10971, Vol. 80, No. 22
0022-538X/06/$08.00+0     doi:10.1128/JVI.01369-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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