Molecular Dynamics Simulations Show How Antibodies May Rescue HIV-1 Mutants Incapable of Infecting Host Cells

High mutation and replication rates of HIV-1 result in the continuous generation of variants, allowing it to adapt to changing host environments. Mutations often have deleterious effects, but variants carrying them are rapidly purged. Surprisingly, a particular variant incapable of entering host cells was found to be rescued by host antibodies targeting HIV-1. Understanding the molecular mechanism of this rescue is important to develop and improve antibody-based therapies. To unravel the underlying mechanisms, we performed fully atomistic molecular dynamics simulations of the HIV-1 gp41 trimer responsible for viral entry into host cells, its entry-deficient variant, and its complex with the rescuing antibody. We find that the Q563R mutation, which the entry-deficient variant carries, prevents the native conformation of the gp41 6-helix bundle required for entry and stabilizes an alternative conformation instead. This is the consequence of substantial changes in the secondary structure and interactions between the domains of gp41. Binding of the antibody F240 to gp41 reverses these changes and re-establishes the native conformation, resulting in rescue. To test the generality of this mechanism, we performed simulations with the entry-deficient L565A variant and antibody 3D6. We find that 3D6 binding was able to reverse structural and interaction changes introduced by the mutation and restore the native gp41 conformation. Viral variants may not only escape antibodies but be aided by them in their survival, potentially compromising antibody-based therapies, including vaccination and passive immunization. Our simulation framework could serve as a tool to assess the likelihood of such resistance against specific antibodies.