Diseases that are transmitted from vertebrate animals to humans are referred to as zoonotic diseases. Although microbial agents such as bacteria and parasites are linked to zoonotic events, viruses account for a high percentage of zoonotic diseases that have emerged. Worryingly, the 21st century has seen a drastic increase in the emergence and re-emergence of viral zoonotic disease. Even though humans and animals have coexisted for millennia, anthropogenic factors have severely increased interactions between the two populations, thereby increasing the risk of disease spill-over. While drivers such as climate shifts, land exploitation and wildlife trade can directly affect the (re-)emergence of viral zoonotic disease, globalisation, geopolitics and social perceptions can directly facilitate the spread of these (re-)emerging diseases. This opinion paper discusses the “intelligent” nature of viruses and their exploitation of the anthropogenic factors driving the (re-)emergence and spread of viral zoonotic disease in a modernised and connected world.

Once merely thought of as the protein responsible for the overall physical nature of the human immunodeficiency virus type 1 (HIV-1), the Gag polyprotein has since been elucidated to have several roles in viral replication and functionality. Over the years, extensive research into the polyproteins’ structure has revealed that Gag can mediate its own trafficking to the plasma membrane, it can interact with several host factors and can even aid in viral genome packaging. Not surprisingly, Gag has also been associated with HIV-1 drug resistance and even treatment failure. Therefore, this review provides an extensive overview of the structural and functional roles of the HIV-1 Gag domains in virion integrity, functionality and infectivity.

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. 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 data are available at Bioinformatics online.

Due to high human immunodeficiency virus type 1 (HIV-1) subtype C infections coupled with increasing antiretroviral treatment failure, the elucidation of complex drug resistance mutational patterns arising through protein co-evolution is required. Despite the inclusion of potent protease inhibitors Lopinavir (LPV) and Darunavir (DRV) in second- and third-line therapies, many patients still fail treatment due to the accumulation of mutations in protease (PR) and recently, Gag. To understand the co-evolutionary molecular mechanisms of resistance in the HIV-1 PR and Gag, we performed 100 ns molecular dynamic simulations on multidrug resistant PR’s when bound to LPV, DRV or a mutated A431V NC|p1 Gag cleavage site (CS). Here we showed that distinct changes in PR’s active site, flap and elbow regions due to several PR resistance mutations (L10F, M46I, I54V, L76V, V82A) were found to alter LPV and DRV drug binding. However, binding was significantly exacerbated when the mutant PRs were bound to the NC|p1 Gag CS. Although A431V was shown to coordinate several residues in PR, the L76V PR mutation was found to have a significant role in substrate recognition. Consequently, a greater binding affinity was observed when the mutated substrate was bound to an L76V-inclusive PR mutant (G_bind: −62.46 ± 5.75 kcal/mol) than without (Gbind: −50.34 ± 6.28 kcal/mol). These data showed that the co-selection of resistance mutations in the enzyme and substrate can simultaneously constrict regions in PR’s active site whilst flexing the flaps to allow flexible movement of the substrate and multiple, complex mechanisms of resistance to occur. Communicated by Ramaswamy H. Sarma