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Our work attempts to bridge the gap between systems biology and more detailed mechanistic studies. While many groups are involved in the generation of large-scale biological datasets, extracting deep insights from these data remains a major challenge. By focusing powerful genetic and mass spectrometry methods to comprehensively define protein-protein, genetic and post-translational modification interaction networks, we have discovered a wealth of new functions, complexes and networks in a variety of organisms. For example, using an affinity tag-purification/mass spectrometry based approach, we have systematically defined a HIV-human physical interactome, which has facilitated a more detailed, structural characterization of several HIV-human protein complexes.