Hosts and viruses are in a constant evolutionary arms race, in which viruses physically interact with many host proteins (immune and non-immune) in order to replicate. Here, we manually classify ~2,500 human virus interacting proteins (VIPs) as a function of their involvement during specific viral replication steps in order to quantify host adaptation across the viral replication cycle. We use an extension of the McDonald-Kreitman test, ABC-MK, to quantify adaptation in human VIPs compared to confounder-matched non-VIPs at different steps of the viral replication cycle. We find significant adaptation at viral replication cycle steps related to entry and release of virions from the cell, with release in particular having experienced extremely high adaptation during human evolution. In contrast to the strategy of host adaptation at entry, which prevents the virus from getting in the cell and replicating in the first place, adaptation at the release stage traps new virions in the cell to prevent continued infection. We explain this unique pattern of adaptation under the framework of a process called intergenerational phenotypic mixing. This adaptation that prevents new viral particles from exiting the cell to continue infection in the host was such a frequent and important strategy in human hosts that the evidence of it can still be found in the form of extremely strong measures of positive selection.
