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

Abstract

Human immunodeficiency virus-1 (HIV-1) exploits the viral gp120 protein and host CD4/CCR5 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 gp120/CD4/CCR5 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 Euarchontoglires (primates and rodents). Although both host genes show similar protein structures conserved in all animals, CD4 gene demonstrates significantly stronger binding affinities in Catarrhini (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 Catarrhini 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 Catarrhini, 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 Catarrhini. 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.