Influenza A virus membrane fusion and disassembly, prerequisite processes for viral infectivity, depend on acidic pH. In a recent study, Zhirnov et al. reported an important finding-that influenza virions are not permeable to protons unless the hemagglutinin (HA) fusion protein is primed by trypsin cleavage. This raises the question of whether in the viral context the M2 ion channel requires priming prior to its activation by low pH. Here, it is hypothesized that both HA and M2 ion channel direct priming by trypsin is required for their sensitization by low pH.