Adaptive mutations enable influenza viruses to evade host immune responses; however, these adaptive amino acid substitutions are often biophysically deleterious and can affect either protein folding or stability. For example, adaptive mutations in influenza virus nucleoprotein (NP) enables escape from human restriction factors but might render the protein unstable. Thus, viruses must balance the costs of NP folding defects with the benefits of escaping host immunity. The authors tested the hypothesis that viruses hijack host chaperones to promote folding of biophysically defective NP escape variants. A destabilized Pro283 NP variant, which enables evasion of the restriction factor Myxovirus resistance protein A, is not tolerated in chaperone-depleted host cells. This suggests that host chaperones rescue biophysically defective viral protein variants and thus influence the fitness cost of destabilized protein variants.