Important note: Information in this article was accurate in 1989. The state of the art may have changed since the publication date.
RAPID IN VITRO SYSTEMS FOR ASSESSING ACTIVITY OF AGENTS AGAINST HTLV-III/LAV
AIDS: Modern Concepts and Therapeutic Challenges. Broder S, ed. New York, Marcel Dekker, p. 303-33, 1987.. Unique Identifier : AIDSLINE ICDB/89650448 Mitsuya H; Matsukura M; Broder S; Clinical Oncology Program, NCI, Bethesda, MD
Abstract:
Development of screening systems for agents active against human T-lymphotropic virus-III/lymphadenopathy-associated virus (HTLV-III/LAV)-related diseases is described, and results are reported for the following: generation of an HTLV-III/LAV cytopathic effect-sensitive T-cell clone; anti-HTLV-III/LAV activities of 2',3'-dideoxynucleosides; inhibition of HTLV-III/LAV DNA synthesis and RNA expression in T cells exposed to the virus; mechanism(s) of antiretroviral activity of 2',3'-dideoxynucleosides; anti-HTLV-III/LAV activities of other 2',3'-dideoxynucleoside analogs; in vitro antiviral effect of combinations of putative drugs; and reversal of 2',3'-dideoxynucleoside protection against the HTLV-III/LAV cytopathic effect by 2'-deoxynucleosides. One of the highest priorities of the drug discovery process is the establishment of a rapid mass screening system for new agents. The authors have used an HTLV-III/LAV cytopathic effect inhibition assay in which an immortalized T-cell line (ATH8) and normal cloned helper-inducer T cells are used as target cells. When ATH8 cells are cultured in a test tube, a pellet is formed whose size reflects the number of viable target cells. Thus, the cytopathic effect is amenable to direct visual inspection. To date, the authors have screened approx 120 nucleoside derivatives. Recently, it was determined that essentially every purine and pyrimidine nucleoside with a 2',3'-dideoxyribose moiety can block the infectivity and cytopathic effects of HTLV-III/LAV in vitro. Southern and Northern hybridization blots demonstrated that no integrated or unintegrated viral DNA or RNA could be detected in ATH8 cells protected by effective dideoxynucleosides, suggesting that the drugs inhibit the virus at the point of cytoplasmic reverse transcription. In assays evaluating the combination of protective drugs, a synergistic antiviral effect of suramin and 3'-azido-3'-deoxythymidine (AZT) and acyclovir and AZT was observed. The use of combinations may allow simultaneous interference with multiple steps of the virus life cycle, lessen the chance of viral resistance by mutation, and forestall certain types of toxicity. Generation of antigen-specific helper-inducer cell lines and the HTLV-III/LAV cytopathic effect inhibition assay are described in an appendix. (53 Refs)
Keywords: Acquired Immunodeficiency Syndrome/*DRUG THERAPY Animal Antiviral Agents/*THERAPEUTIC USE Cytopathogenic Effect, Viral/DRUG EFFECTS Dideoxynucleosides/THERAPEUTIC USE Drug Screening DNA Replication/DRUG EFFECTS Gene Expression Regulation/DRUG EFFECTS Human HIV/*DRUG EFFECTS/GENETICS RNA, Viral/GENETICS MONOGRAPH REVIEW REVIEW, TUTORIAL
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Important note: Information in this article was accurate in 1989. The state of the art may have changed since the publication date.
