We are investigating the mechanism of action of SPL7013 (VivaGel®), a candidate microbicide that blocks HIV entry of host cells¹ . Microbicides are topically-applied compounds designed to be managed by women for their own protection against contracting human immunodeficiency virus (HIV) and other sexually transmitted infections. The first microbicides in development did not prevent HIV infection in clinical trials and were sometimes toxic^2,3. Limited specificity including similar affinity for viral protein targets and host cell proteins⁴, as well as lack of chemical and structural homogeneity could explain their lack of efficacy and high toxicity. The candidate microbicide in our study, SPL7013, is a member of the dendrimer family comprising large, branched molecules with the potential to mimic interfaces favourable for protein binding⁵. The SPL7013 dendrimer (16.5 kDa) has negatively-charged and hydrophobic surface functional groups likely targeting exposed positive regions on HIV envelope glycoproteins, although its mechanism of action at the molecular level has not been fully elucidated. We are using small angle X-ray scattering (SAXS) in conjunction with molecular modelling and surface plasmon resonance (SPR) to characterise the nature of HIV-1 envelope (env) proteins binding to SPL7013 dendrimer, and comparing to interactions with non-branched microbicide compounds. SAXS analysis of SPL7013 in complex with HIV-1 env protein suggests a discrete stoichiometry supportive of a specific interaction, which was not observed for PRO2000, an ineffective, linear polyanion microbicide with similar but distinct surface groups to SPL7013. We have also determined that SPL7013 interacts with HIV env proteins from different infectious HIV strains with similar affinities, and has a 20- to 100-fold higher binding affinity for HIV env than the host cell receptor, CD4, which is required for viral entry on infection.