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Motivation Commonly, protease inhibitor failure is characterized by the development of multiple protease resistance mutations (PRMs). While the impact of PRMs on therapy failure are understood, the introduction of Gag mutations with protease remains largely unclear. Results Here, we utilized phylogenetic analyses and Bayesian network learning as tools to understand Gag-protease coevolution and elucidate the pathways leading to Lopinavir failure in HIV-1 subtype C infected patients. Our analyses indicate that while PRMs coevolve in response to drug selection pressure within protease, the Gag mutations added to the existing network while specifically interacting with known Lopinavir failure PRMs. Additionally, the selection of mutations at specific positions in Gag-protease suggests that these coevolving mutational changes occurs to maintain structural integrity during Gag cleavage. Supplementary information Supplementary data are available at Bioinformatics online.