NEW YORK (Reuters Health) - At subcytotoxic concentrations, the experimental bis-anthracycline antibiotic WP631 effectively suppresses HIV-1 expression in cell culture by inhibiting transactivation of the HIV-1 regulatory protein Tat, according to a new study. At higher concentrations, the compound has antineoplastic properties.
WP631 holds promise both as a “lead compound for a new type of HIV-1 inhibitor and as a bimodal agent for the treatment of AIDS-related lymphoma,” Dr. Olaf Kutsch from the University of Alabama at Birmingham told Reuters Health.
In the May issue of Antimicrobial Agents and Chemotherapy, Dr. Kutsch and colleagues report that WP631 downregulates HIV-1 expression by 70% in JNLG and J89G cells “without any apparent cytotoxicity.” This level of HIV-1 inhibition is comparable to the established Tat inhibitor Ro24-7249, the investigators point out.
In HIV-1-infected cultured peripheral blood mononuclear cells (PBMCs), WP631 inhibited HIV-1 replication by 80% to 90%, independent of HIV-1 viral strain.
WP631-mediated HIV-1 inhibition appears to be the result of Tat transactivation inhibition. “To our knowledge, this is the first description of a DNA bis-intercalator that specifically interferes with Tat transactivation,” Dr. Kutsch and colleagues note.
In comments to Reuters Health, Dr. Kutsch noted that WP631’s anticancer properties could improve the treatment of AIDS-related malignancies.
“Treatment of AIDS-related malignancies, in particular AIDS-related lymphoma, is very challenging and treatment outcomes are generally not encouraging,” he explained. “The combined toxicities of the cancer therapy and the ongoing antiretroviral therapy are thought to drastically reduce the chance of a positive treatment outcome, but cessation of antiretroviral therapy is feared to result in a rebounding viremia, with all its adverse effects for the patient.”
“Compounds such as WP631 could control the virus while exerting their anti-tumor effect, thereby hopefully reducing the overall treatment toxicity,” he added.
Source: Antimicrob Agents Chemother 2004;48:1652-1663. [ Google search on this article ]
MeSH Headings:DNA-Binding Proteins: Transcription Factors: Viral Proteins: Viral Regulatory Proteins: Trans-Activators: Gene Products, tatCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
