Genomic coevolution of papillomavirus and immune system in placental mammals indicates the role of IFN-gamma in the emergence of new variants

Papillomaviruses (PVs) are causative agents for warts and cancers in different parts of the body in the mammalian lineage. Therefore, these viruses are proposed as model organisms to study host immune responses to pathogens causing chronic infections. The virus-associated cancer progression depends on two integral processes namely angiogenesis and immune response (AIR). The angiogenesis process aids in tumour progression through vessel formation and maturation but the host immune response, in contrast, makes every attempt to eliminate pathogens and thereby maintain healthy tissues. However, the evolutionary contribution of individual viral genes and host AIR genes in carcinogenesis is yet to be explored. Here, we applied the evolutionary genomics approach to find correlated evolution between six PV genes and 23 host AIR-related genes. We estimated that interferon (IFN)-gamma is the only host gene evolving in a correlated manner with all six PV genes under study. Furthermore, three PV genes, such as L2, E6 and E7, are found to interact with two thirds of host AIR-related genes. Moreover, a combined differential gene expression analysis and network analysis showed that inflammatory cytokine IFN-gamma is the key regulator of hub genes in the protein-protein interaction network of the differentially expressed genes. Functional enrichment of these hub genes is consistent with their established role in different cancers and viral infections. Overall, we conclude that IFN-gamma maintains selective pressure on mammalian PV genes and seems to be a potential biomarker for PV-related cancers. This study demonstrates the evolutionary importance of IFN-gamma in deciding the fate of carcinogenic PV variants. We have performed co-evolutionary analysis combined with expression analysis to explore the evolutionary contribution of individual host AIR and PV genes. We observed that interferon (IFN)-gamma co-evolves with six PV genes and may contribute to virus clearance and new PV variant emergence. Moreover, PV genes such as E6, E7 and L2 co-evolve with two thirds of host AIR genes and are likely to participate in cancer progression. Our study also support that the L2-based epitopes may be promising vaccine candidates against wide PV infections.