Inhibition of HIV-1 replication by nanobodies targeting tetraspanin CD9

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2024-09-13 DOI:10.1016/j.isci.2024.110958

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Abstract

HIV-1 alters the dynamics and distribution of tetraspanins, a group of proteins integral to membrane organization, to facilitate both entry and egress. Notably, the tetraspanin CD9 is dysregulated during HIV-1 infection, correlating with multifaceted effects on viral replication. Here, we generated llama-derived nanobodies against CD9 to restrict HIV-1 replication. We immunized llamas with recombinant large extracellular loop of CD9 and identified eight clonally distinct nanobodies targeting CD9, each exhibiting a range of affinities and differential binding to cell surface-expressed CD9. Notably, nanobodies T2C001 and T2C002 demonstrated low nanomolar affinities and exhibited differential sensitivities against endogenous and overexpressed CD9 on the cell surface. Although CD9-directed nanobodies did not impede the early stages of HIV-1 life cycle, they effectively inhibited virus-induced syncytia formation and virus replication in T cells and monocyte-derived macrophages. This discovery opens new avenues for host-targeted therapeutic strategies, potentially augmenting existing antiretroviral treatments for HIV-1.

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靶向四跨蛋白 CD9 的纳米抗体抑制 HIV-1 复制

HIV-1改变了四跨蛋白的动态和分布，而四跨蛋白是膜组织中不可或缺的一组蛋白质，可促进病毒的进入和排出。值得注意的是，四跨蛋白 CD9 在 HIV-1 感染期间失调，对病毒复制产生了多方面的影响。在这里，我们生成了针对 CD9 的源于美洲驼的纳米抗体，以限制 HIV-1 的复制。我们用重组的CD9大细胞外环对骆驼进行了免疫，并鉴定出了8种不同克隆的靶向CD9的纳米抗体，每种抗体都表现出了不同的亲和力以及与细胞表面表达的CD9的不同结合力。值得注意的是，纳米抗体 T2C001 和 T2C002 表现出低纳摩尔亲和力，并对细胞表面的内源性和过表达 CD9 表现出不同的敏感性。虽然 CD9 定向纳米抗体不能阻止 HIV-1 生命周期的早期阶段，但它们能有效抑制病毒诱导的合胞体形成以及病毒在 T 细胞和单核巨噬细胞中的复制。这一发现为宿主靶向治疗策略开辟了新途径，有可能增强现有的 HIV-1 抗逆转录病毒疗法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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