Stronger binding affinities of gp120/CD4 in Catarrhini provide insights into HIV/host interactions

Human immunodeficiency virus-1 (HIV-1) exploits the viral <i>gp120</i> protein and host <i>CD4</i>/<i>CCR5</i> receptors for the pandemic infection to humans. The host co-receptors of not only humans but also several primates and HIV-model mice can interact with the HIV receptor. However, the molecular mechanisms of these interactions remain unclear. Using Shaik et al. (2019)'s <i>gp120/CD4/CCR5</i> structure of HIV-1B and human, here, we investigate the molecular dynamics between HIV sub-lineages (B, C, N, and O) and potential hosts in <i>Euarchontoglires</i> (primates and rodents). Although both host genes show similar protein structures conserved in all animals, <i>CD4</i> gene demonstrates significantly stronger binding affinities in <i>Catarrhini</i> (apes and Old-World monkeys). Its known candidate residues interacted with gp120 fail to explain these affinity variations. Therefore, we identified novel candidate sites under positive selection on the <i>Catarrhini</i> lineage. Among four positively selected sites, residue R58 in humans is located within an antigen-antibody binding domain, exhibiting apomorphic amino acid substitutions as Arginine (R) in <i>Catarrhini</i>, which are mutually exclusive to the other animals where Lysine (K) is prevalent. Applying for artificial mutation test, we validated that K to R substitutions can lead stronger binding affinities of <i>Catarrhini</i>. Ecologically, these dynamics may relate to shared equatorial habitats in Africa and Asia. Our findings suggest a new candidate site R58 driven by the lineage-specific evolution as a molecular foundation on HIV infection.