XI International HIV Drug Resistance Workshop: Basic Principles and Clinical Implications


Seville, Spain, 2–5 July 2002


A NOVEL HIV-1 INTEGRASE INHIBITOR MEDIATES SUSTAINED SUPPRESSION OF VIRAL REPLICATION AND CD4 DEPLETION IN A SHIV RHESUS MACAQUE MODEL OF INFECTION

Antivir Ther. 2002;7(Suppl 1):S3 (abstract no. 1)

D Hazuda and the HIV-1 Integrase Inhibitor Discovery Team
Merck Research Laboratories, West Point, Pa., USA

The increasing incidence of resistance to HIV-1 therapy observed in both treatment-experienced patients and in primary transmission emphasizes the need for new, well-tolerated agents for patients at all stages of disease. Integrase is the third of the HIV-1 enzymes required for viral replication. However, unlike the viral protease and reverse transcriptase, the development of biologically effective integrase inhibitors has been unsuccessful to date. During HIV-1 infection, integrase catalyzes the insertion of the HIV-1 DNA into the genome of the host cell. Integration requires a series of reactions that include assembly of a stable complex with the viral DNA, 3' endonucleolytic processing of the viral DNA ends, and strand transfer or joining of the viral and cellular DNAs. We previously demonstrated that 4-aryl-2,4-diketobutanoic acids (DKAs) inhibit strand transfer in both enzymatic assays and infected cells, and are effective as inhibitors of integration and HIV-1 replication in vitro. Modification of these inhibitors has led to the identification of a series of novel, condensed heterocyclic compounds with improved potency and pharmacokinetic characteristics suitable for clinical development. The compounds are efficacious against multidrugresistant HIV-1 variants, retain potency in human serum and are synergistic with both reverse transcriptase and protease inhibitors. The inhibitors exhibit comparable activity against SIV and HIV-1 integrase in biochemical assays and are effective inhibitors of SIV (but not MuLv) viral replication. We, therefore, evaluated a representative integrase inhibitor from this series in a pre-clinical efficacy study using a rhesus macaque infection model with SHIV 89.6P. Oral administration of the compound as a single agent effectively inhibited viral replication (1 to 3 log decrease in vRNA) and preserved CD4 levels. Viral inhibition was sustained throughout the 75-day course of compound administration. These observations provide the first demonstration of biological activity for an inhibitor of HIV-1 integrase in vivo.

PRESENTING AUTHOR: D Hazuda

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2002-07-02
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