4th International AIDS Society Conference on HIV Pathogenesis and Treatment Sydney, Australia - July 22 - 25, 2007

DEVELOPMENT OF DENDRIMER-BASED MICROBICIDES

IAS Conf HIV Pathog Treat 2007 Jul 22-25;4th: Abstract No. MOPDA04

Tachedjian G.¹, Tyssen D.¹, Henderson S.², Lowe M.², Zanin M.¹, Paull J.², Krippner G.², McCarthy T.², Wesselingh S. ^1
1Macfarlane Burnet Institute, Melbourne, Australia, ²Starpharma Pty Ltd, Melbourne, Australia

OBJECTIVES: The dendrimer SPL7013 is undergoing clinical evaluation as a vaginal microbicide. SPL7013 has broad-spectrum activity against HIV-1, HSV-1 and HSV-2, blocking viral entry into target cells. Dendrimers are a relatively new class of macromolecule characterized by highly branched, 3-D architectures which contain multiple surface groups. The objective of this study was to investigate the efficacy of SPL7013 against a range of HIV isolates and to determine whether HIV strains that are resistant to SPL7013 could be selected in vitro.

METHODS: SPL7013 was tested against a number of HIV-1 clades (including A, B, C, D, E/A and O), HIV-2 and HIV-1 primary isolates that utilize the CXCR4 and CCR5 co-receptors in the TZM-bl indicator cell line. HIV-1-resistant strains were selected after serial in vitro passage of HIV-1 NL4.3 in the presence of escalating concentrations of SPL7013.

RESULTS: SPL7013 was equally effective against CCR5- and CXCR4-utilising HIV-1 from a variety of HIV-1 clades and HIV-2. Propagation of HIV-1 NL4.3 through 44 passages in MT-2 cells in the presence of SPL7013 resulted in only a 2-3-fold increase in virus IC₅₀ compared to wild type virus. Some cross resistance to dextran sulphate and Enfuvirtide (T-20) was observed, while there was no significant cross resistance to AMD3100.

CONCLUSIONS: We have demonstrated that SPL7013 is active against a variety of HIV isolates from various clades and utilising both R5 and X4 co-receptors and that it is difficult to generate in vitro HIV-1 resistance to this dendrimer.

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2007-07-22
MOPDA04
Models for Mucosal Immunity and Transmission

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