Influenza-A-virus (IAV) is one of the common threats to humankind since 1918. The viral proteome is frequently substituted leading to new strains and recurrent pandemics. Despite knowing the effects of single amino acid substitutions on individual viral proteins, effects of collective substitutions on viral infection remain elusive. Here, we addressed the question whether the “consistent amino substitutions” occur in consortium on functional domains and protein-protein interaction (PPI) sites, impacting overall viral infection and host immune responses. By definition, “consistent substitutions” occur on “all” the IAV strains isolated in a particular year. Big protein data (563370 sequences and 9824 PPI) and bioinformatics techniques were exploited to address this question. Total one-hundred-and-five “consistent substitutions” were mapped on IAV proteome. Fifty of those emerged on viral functional domains and PPIs, engaged in the specific stages of IAV infection, namely, i) cell surface entry and exit, ii) nuclear import, vRNP assembly and nuclear export and iii) antagonizing immune responses. The study for the first time showed that consortium of “consistent substitutions” emerged on protein functional domains and PPIs, impacting specific stages of viral infection, rather than a single protein, and presumably navigate viral escape from human immune response.