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Antimicrobial Agents and Chemotherapy, February 2003, p. 501-508, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.501-508.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Toward the Development of a Virus-Cell-Based Assay for the Discovery of Novel Compounds against Human Immunodeficiency Virus Type 1

Martin E. Adelson,^1, Annmarie L. Pacchia,^1,2 Malvika Kaul,^1,2, Robert F. Rando,³ Yacov Ron,¹ Stuart W. Peltz,^1,3 and Joseph P. Dougherty^1*

Department of Molecular Genetics and Microbiology, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854,¹ Graduate Program in Microbiology and Molecular Genetics, Rutgers University, New Brunswick, New Jersey 08903,² PTC Therapeutics, Inc., South Plainfield, New Jersey 07080³

Received 26 June 2002/ Returned for modification 3 October 2002/ Accepted 14 November 2002

The emergence of human immunodeficiency virus type 1 (HIV-1) strains resistant to highly active antiretroviral therapy necessitates continued drug discovery for the treatment of HIV-1 infection. Most current drug discovery strategies focus upon a single aspect of HIV-1 replication. A virus-cell-based assay, which can be adapted to high-throughput screening, would allow the screening of multiple targets simultaneously. HIV-1-based vector systems mimic the HIV-1 life cycle without yielding replication-competent virus, making them potentially important tools for the development of safe, wide-ranging, rapid, and cost-effective assays amenable to high-throughput screening. Since replication of vector virus is typically restricted to a single cycle, a crucial question is whether such an assay provides the needed sensitivity to detect potential HIV-1 inhibitors. With a stable, inducible vector virus-producing cell line, the inhibitory effects of four reverse transcriptase inhibitors (zidovudine, stavudine, lamivudine, and didanosine) and one protease inhibitor (indinavir) were assessed. It was found that HIV-1 vector virus titer was inhibited in a single cycle of replication up to 300-fold without affecting cell viability, indicating that the assay provides the necessary sensitivity for identifying antiviral molecules. Thus, it seems likely that HIV-1-derived vector systems can be utilized in a novel fashion to facilitate the development of a safe, efficient method for screening compound libraries for anti-HIV-1 activity.

Present address: Department of Research and Development, Medical Diagnostic Laboratories, Mt. Laurel, NJ 08054.

Present address: Department of Pharmacology, Robert Wood Johnson Medical School, Piscataway, NJ 08854.

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