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Journal of Virology, January 2004, p. 922-929, Vol. 78, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.2.922-929.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Small-Molecule Inhibition of Human Immunodeficiency Virus Type 1 Replication by Specific Targeting of the Final Step of Virion Maturation

Jing Zhou,1 Xiong Yuan,2 David Dismuke,1 Brett M. Forshey,1 Christopher Lundquist,1 Kuo-Hsiung Lee,3 Christopher Aiken,1* and Chin Ho Chen2,{dagger}

Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232,1 Department of Microbiology, Meharry Medical College, Nashville, Tennessee 37208,2 Division of Medicinal Chemistry, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 275993

Received 5 August 2003/ Accepted 3 September 2003

Despite the effectiveness of currently available human immunodeficiency virus type 1 (HIV-1) therapies, a continuing need exists for new drugs to treat HIV-1 infection. We investigated the mechanism by which 3-O-{3',3'-dimethylsuccinyl}-betulinic acid (DSB) inhibits HIV-1 replication. DSB functions at a late stage of the virus life cycle but does not inhibit the HIV-1 protease in vitro or interfere with virus assembly or release. DSB specifically delays the cleavage of Gag between the capsid (CA) and p2, resulting in delayed formation of the mature viral core and reduced HIV-1 infectivity. Replication of simian immunodeficiency virus (SIV) was resistant to DSB; however, a chimeric SIV carrying CA-p2 sequences from HIV-1 was inhibited by the drug, indicating that susceptibility to DSB maps to the CA-p2 region of the HIV-1 Gag protein. A single point mutation at the CA-p2 cleavage site of HIV-1 conferred strong resistance to DSB, confirming the target of the drug. HIV-1 strains that are resistant to a variety of protease inhibitors were sensitive to DSB. These findings indicate that DSB specifically protects the CA-p2 cleavage site from processing by the viral protease during virion maturation, thereby revealing a novel mechanism for pharmacologic inhibition of HIV-1 replication.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Vanderbilt University School of Medicine, A-5301 Medical Center North, Nashville, TN 37232-2363. Phone: (615) 343-7037. Fax: (615) 343-7392. E-mail: chris.aiken{at}mcmail.vanderbilt.edu.

{dagger} Present address: Department of Surgery, Duke University Medical Center, Durham, NC 27710.

Journal of Virology, January 2004, p. 922-929, Vol. 78, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.2.922-929.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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