Coevolutionary Patterns in HIV-1 Pre-integration Complex Offer Insights Into Protein Structural Constraints

Recognition of viral epitopes by the host immune system plays a pivotal role in controlling viral infection, while at the same time exerting selective pressure for escape mutations, which in turn leads to many epitopes evolving faster than the adjacent regions. Some epitope regions appear to be highly conserved despite the strong immune pressure due to functional and/or structural constraints acting on them. Yet, we still have relatively little understanding of the nature of protein structural and functional constraints operating on epitope regions. Here we identify coevolving epitope regions that have high functional and/ or structural constraints. We examined patterns of coevolution of protein segment pairs between Integrase-Reverse Transcriptase, Integrase-Vpr, and Reverse Transcriptase-Vpr protein interactions pairs in HIV-1 pre-integration complex. Our coevolutionary and structural analysis shows that protein regions with strong multiple coevolutionary constraints with few regions are located in structurally conserved regions (i.e., those with well-defined secondary structures). Meanwhile, protein regions with strong multiple coevolutionary constraints with many regions are clustered in the structurally flexible regions (regions with high B-factor) of the proteins and regions with high conformational diversity (relative mobility in the collective dynamics). On the other hand, protein regions with weak coevolutionary signals are clustered in structurally disordered regions. Identifying viral epitope regions that harbor strong constraints against escape mutations is important in development of vaccines that can induce immune responses against multiple conserved epitopes. This analysis also offers important insights into molecular evolution of protein interactions.