(595g) Molecular Models Indicate Stronger Binding of HIV-1 to Co-Receptor CXCR4 Compared to CCR5 at a Viral Population Level

In order for Human Immunodeficiency Virus Type 1 (HIV-1) to enter host cells, its “Env” surface glycoprotein engages a primary cellular receptor, CD4, and then one of two possible co-receptors, CCR5 or CXCR4. The amino acid sequence of HIV-1 Env is either CCR5-tropic, CXCR4-tropic, or dual-tropic. Transmitted/founder strains of HIV-1, which seed new human infections, are usually CCR5-tropic. However, as HIV-1 infection progresses, viral variants can arise that have CXCR4- or dual-tropism. We gathered nearly all sequences of Env in the Los Alamos National Laboratory HIV Sequence Database. We utilized an experimentally validated computational scoring function to calculate the free energy of interaction between each of these Envs and either CCR5 or CXCR4. We found that regardless of tropism, Env typically binds CXCR4 more strongly than CCR5. Conversely, CXCR4-tropic Envs bound to both co- receptors more strongly than CCR5-tropic Envs.

We further employed physics-based all-atom simulations of protein-protein interaction to calculate the free energy between each of these Envs and either CCR5 or CXCR4, in which the co-receptor was embedded in a lipid bilayer. We engineered CXCR4-tropic mutations in CCR5- tropic Env. We found that such mutations caused disruption of the stability of Env when bound to CXCR4 but not to CCR5.

Based on these results, we predicted that most CXCR4-tropic Envs bind CCR5 too strongly and most CCR5- tropic Envs bind CXCR4 too weakly for efficient infection. We predicted that an optimal degree of binding affinity and flexibility between Env and its co-receptor is required for efficient infection. The optimal affinity of Env for each co-receptor is different, possibly explaining why not all Envs bind both CCR5 and CXCR4.

Ultimately, our results shed new insights into the sequence population-level thermodynamics and molecular-level mechanisms of HIV-1 infection, supporting further research into novel or improved therapeutics to treat people infected with HIV-1.