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Background: The development of antiviral drugs has provided crucial new means to mitigate or relieve the debilitating effects of many viral pathogens. Regular use of these drugs has led to generation of resistant strains, making the control of many viral infections very difficult, particularly in HIV-seropositive and AIDS patients. A rich source for the discovery of new HIV infection inhibitors has been, and continues to be, the 'mining' of the large diversity of compounds already available in nature, and specifically those from botanical extracts., Methods: Using a newly developed direct binding assay with mass spectrometry technology (direct analysis in real-time time-of-flight mass spectrometry), we were able to show that compounds present in extracts of elderberry, cinnamon and green tea bind to and block HIV type-1 (HIV-1) infection in target cells., Results: The compounds that blocked HIV-1 infection were flavonoids and A-type proanthocyanidins. The 50% inhibitory concentration values of these extracts ranged from 0.5 to 201 microg/ml for four different HIV-1 serotypes. Interaction matrices with the elderberry extract and enfuvirtide, a peptide HIV-1 fusion inhibitor, revealed significant super additive effects. This indicates that the compounds in elderberry that prevent HIV-1 infection are likely to bind to viral glycoproteins other than gp41 (the binding site for enfuvirtide)., Conclusions: Optimized elderberry, green tea and cinnamon extracts rich in certain flavonoid compounds were shown to block HIV-1 entry and infection in GHOST cells. As such, these types of botanical extracts could provide a starting point for the development of possible safe and reliable cotherapies for HIV-1-positive individuals, as well as for the identification of new small molecules as leading drug candidates for HIV-1 therapeutics and microbicides.