A Look Inside HIV Resistance through Retroviral Protease Interaction Maps

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Abstract
Retroviruses affect a large number of species, from fish and birds to mammals and humans, with global socioeconomic negative impacts. Here the authors report and experimentally validate a novel approach for the analysis of the molecular networks that are involved in the recognition of substrates by retroviral proteases. Using multivariate analysis of the sequence-based physiochemical descriptions of 61 retroviral proteases comprising wild-type proteases, natural mutants, and drug-resistant forms of proteases from nine different viral species in relation to their ability to cleave 299 substrates, the authors mapped the physicochemical properties and cross-dependencies of the amino acids of the proteases and their substrates, which revealed a complex molecular interaction network of substrate recognition and cleavage. The approach allowed a detailed analysis of the molecular–chemical mechanisms involved in substrate cleavage by retroviral proteases. Retroviruses are associated with a broad range of diseases that include tumor formation, neurological disorders, and immunodeficiency syndromes, including those of HIV. The extraordinary mutational plasticity of HIV-1 causes the rapid appearance of highly diverse quasi-species in a very short time, leading to severe problems with drug resistance. We here present and validate experimentally a novel approach for the analysis of the molecular interaction networks involved in the recognition process of substrates by natural and drug-resistant retroviral proteases. By combining a large number of wild-type and mutant retroviral proteases from nine different viral species, and their interactions with a large number of substrates, we have created a unified model incorporating all the proteases' mutational space. Our results reveal that a complex physicochemical interaction network is involved in substrate recognition and cleavage by aspartate proteases and unravel detailed molecular mechanisms involved in drug resistance. These findings provide novel implications for understanding important features of HIV resistance and raise the possibility of developing completely novel strategies for the design of protease inhibitors that will remain effective over time despite rapid viral evolution.