Li Vladimir, Lee Chul, Park TaeHyun, Jarvis Erich D, Kim Heebal
Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Republic of Korea.
Laboratory of Neurogenetics of Language, The Rockefeller University, New York, NY, USA.
Infect Dis Model. 2024 Oct 19;10(1):287-301. doi: 10.1016/j.idm.2024.10.003. eCollection 2025 Mar.
Human immunodeficiency virus-1 (HIV-1) exploits the viral protein and host / 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 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 (primates and rodents). Although both host genes show similar protein structures conserved in all animals, gene demonstrates significantly stronger binding affinities in (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 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 , 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 . 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.
人类免疫缺陷病毒1型（HIV-1）利用病毒蛋白和宿主受体对人类进行大规模感染。不仅人类，还有几种灵长类动物和HIV模型小鼠的宿主共受体都能与HIV受体相互作用。然而，这些相互作用的分子机制仍不清楚。在此，我们利用沙伊克等人（2019年）的HIV-1B与人类的结构，研究HIV亚谱系（B、C、N和O）与（灵长类动物和啮齿动物）潜在宿主之间的分子动力学。尽管两种宿主基因在所有动物中都显示出相似的保守蛋白质结构，但（猿类和旧世界猴）的基因表现出明显更强的结合亲和力。其已知的与gp120相互作用的候选残基无法解释这些亲和力差异。因此，我们在（该）谱系上鉴定出了处于正选择下的新候选位点。在四个正选择位点中，人类的R58残基位于抗原-抗体结合域内，在（该域）中表现为精氨酸（R）的独特氨基酸取代，这与其他以赖氨酸（K）为主的动物相互排斥。通过人工突变试验，我们验证了K到R的取代可导致（该域）更强的结合亲和力。从生态学角度来看，这些动力学可能与非洲和亚洲共有的赤道栖息地有关。我们的研究结果表明，由谱系特异性进化驱动的新候选位点R58是HIV感染的分子基础。
