title: Toward the development of a virus-cell-based assay for the discovery of novel compounds against human immunodeficiency virus type 1.
abstract: 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.
authors.affiliation: Department of Molecular Genetics, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Adelson
authors.forename: Annmarie L
authors.initials: AL
authors.lastname: Pacchia
authors.forename: Malvika
authors.initials: M
authors.lastname: Kaul
authors.forename: Robert F
authors.initials: RF
authors.lastname: Rando
authors.forename: Yacov
authors.initials: Y
authors.lastname: Ron
authors.forename: Stuart W
authors.initials: SW
authors.lastname: Peltz
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Dougherty
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006367:HeLa Cells; D006801:Humans
chemical_list: D019380:Anti-HIV Agents