Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute , Boston, Massachusetts, USA.
Department of Microbiology, Harvard Medical School , Boston, Massachusetts, USA.
J Virol. 2023 Nov 30;97(11):e0117123. doi: 10.1128/jvi.01171-23. Epub 2023 Oct 27.
CD4-mimetic compounds (CD4mcs) are small-molecule inhibitors of human immunodeficiency virus (HIV-1) entry into host cells. CD4mcs target a pocket on the viral envelope glycoprotein (Env) spike that is used for binding to the receptor, CD4, and is highly conserved among HIV-1 strains. Nonetheless, naturally occurring HIV-1 strains exhibit a wide range of sensitivities to CD4mcs. Our study identifies changes distant from the binding pocket that can influence the susceptibility of natural HIV-1 strains to the antiviral effects of multiple CD4mcs. We relate the antiviral potency of the CD4mc against this panel of HIV-1 variants to the ability of the CD4mc to activate entry-related changes in Env conformation prematurely. These findings will guide efforts to improve the potency and breadth of CD4mcs against natural HIV-1 variants.
CD4 模拟化合物 (CD4mcs) 是一种小分子抑制剂，可阻止人类免疫缺陷病毒 (HIV-1) 进入宿主细胞。CD4mcs 靶向病毒包膜糖蛋白 (Env) 刺突上的一个口袋，该口袋用于与受体 CD4 结合，并且在 HIV-1 株之间高度保守。尽管如此，天然 HIV-1 株对 CD4mcs 的敏感性差异很大。我们的研究确定了远离结合口袋的变化，这些变化可能会影响天然 HIV-1 株对多种 CD4mcs 的抗病毒作用的敏感性。我们将针对该组 HIV-1 变体的 CD4mc 的抗病毒效力与 CD4mc 过早激活 Env 构象与进入相关的变化的能力相关联。这些发现将指导提高针对天然 HIV-1 变体的 CD4mcs 的效力和广度的努力。
