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J. Biol. Chem., Vol. 281, Issue 39, 28699-28711, September 29, 2006

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Inhibition of HIV-1 Replication by Amphotericin B Methyl Ester

SELECTION FOR RESISTANT VARIANTS^*

Abdul A. Waheed, Sherimay D. Ablan, Marie K. Mankowski, James E. Cummins, Roger G. Ptak, Carl P. Schaffner^¶, and Eric O. Freed¹

From the Virus-Cell Interaction Section, HIV Drug Resistance Program, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702-1201, the Infectious Disease Research Department, Southern Research Institute, Frederick, Maryland 21701, and the ^¶Department of Microbiology and Biochemistry, Waksman Institute, Rutgers, the State University of New Jersey, New Brunswick, New Jersey 08903

Membrane cholesterol plays an important role in human immunodeficiency virus type 1 (HIV-1) particle production and infectivity. Here, we have investigated the target and mechanism of action of a cholesterol-binding compound, the polyene antifungal antibiotic amphotericin B methyl ester (AME). We found that AME potently inhibited the replication of a highly divergent panel of HIV-1 isolates in various T-cell lines and primary cells irrespective of clade or target cell tropism. The defects in HIV-1 replication caused by AME were due to profoundly impaired viral infectivity as well as a defect in viral particle production. To elucidate further the mechanism of action of AME, we selected for and characterized AME-resistant HIV-1 variants. Mutations responsible for AME resistance mapped to a highly conserved and functionally important endocytosis motif in the cytoplasmic tail of the transmembrane glycoprotein gp41. Interestingly, truncation of the gp41 cytoplasmic tail in the context of either HIV-1 or rhesus macaque simian immunodeficiency virus also conferred resistance to AME. The infectivity of HIV-1 virions bearing murine leukemia virus or vesicular stomatitis virus glycoproteins was unaffected by AME. Our data define the target and mechanism of action of AME and provide support for the concept that cholesterol-binding compounds should be pursued as antiretroviral drugs to disrupt HIV-1 replication.

Received for publication, April 14, 2006 , and in revised form, June 5, 2006.

^* This work was supported by the Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Virus-Cell Interaction Section, HIV Drug Resistance Program, NCI-Frederick, NIH, Bldg. 535, Rm. 108, Frederick, MD 21702-1201. Tel.: 301-846-6223; Fax: 301-846-6777; E-mail: efreed{at}mail.nih.gov.

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