3rd International AIDS Society Conference on HIV Pathogenesis and Treatment Rio de Janeiro - July 24 - 27, 2005

NOVEL COMPOUNDS THAT INHIBIT HIV REPLICATION BY ACTING THROUGH INHIBITION OF HIV REV FUNCTION

IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract No. WePp0106

Rekosh D.¹, Ptak R.², Hammarskjold M.-L.^1
1 University of Virginia, Department of Microbiology, Charlottesville, VA, United States of America, ² Southern Research Institue, Department of Infectious Disease Research, Frederick, MD, United States of America

INTRODUCTION: Current drugs in use for the treatment of AIDS target viral enzymatic activities. Because the development of drug resistance commonly occurs, there remains a need to develop alternative therapies that target other essential viral activities. We have recently identified several small molecule compounds that appear to inhibit HIV replication by interfering with Rev function. The Rev protein is absolutely essential for viral replication, since in the absence of Rev, genomic RNA and several other HIV mRNAs cannot exit the nucleus. When Rev is inhibited, viral structural proteins are not made and the infectious cycle cannot continue.

METHODS: A cell-based screening assay to identify compounds that inhibit HIV Rev function was utilized. This assay is based on a novel cell line which contains the HIV gag/gagpol genes expressed in a way that is totally dependent on the presence of a functional rev gene. In the presence of Rev, virus-like particles are secreted into the medium and can be easily measured by a p24 ELISA. Interference with Rev function results in loss of particle production. The cell line was used to screen 40,000 compounds.

RESULTS: 192 compounds were selected from the original screen because they showed more than 50% inhibition at a 10 uM concentration. These compounds were then tested in 3 and 6 point dose response and cytotoxicity assays, including a 5-day toxicity assay in MT-4 cells. From this screen 12 compounds emerged as bona fide actives. Each of the 12 compounds were then tested in a dual luciferase Rev assay, in viral replication assays in PBMCs and in a U1 cell latency re-activation assay. Many of the compounds show good anti-viral activity in the uM range and also score as Rev inhibitors.

CONCLUSIONS: These compounds are promising leads as therapeutic candidates that target HIV replication through inhibition of Rev function.

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050724
Basic | WePp0106 | David Rekosh
New Antiretroviral Targets And Compounds

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