Gai Yanxin, Duan Sizhu, Wang Shiqi, Liu Kaifeng, Yu Xin, Yang Chumeng, Li Guoqing, Zhou Yan, Yu Bin, Wu Jiaxin, Wang Chu, Yu Xianghui
National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, China.
Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China.
Viruses. 2024 Mar 22;16(4):490. doi: 10.3390/v16040490.
One of the major functions of the accessory protein Vif of human immunodeficiency virus type 1 (HIV-1) is to induce the degradation of APOBEC3 (A3) family proteins by recruiting a Cullin5-ElonginB/C-CBFβ E3 ubiquitin ligase complex to facilitate viral replication. Therefore, the interactions between Vif and the E3 complex proteins are promising targets for the development of novel anti-HIV-1 drugs. Here, peptides are designed for the Vif-CBFβ interaction based on the sequences of Vif mutants with higher affinity for CBFβ screened by a yeast surface display platform. We identified two peptides, VMP-63 and VMP-108, that could reduce the infectivity of HIV-1 produced from A3G-positive cells with IC50 values of 49.4 μM and 55.1 μM, respectively. They protected intracellular A3G from Vif-mediated degradation in HEK293T cells, consequently increasing A3G encapsulation into the progeny virions. The peptides could rapidly enter cells after addition to HEK293T cells and competitively inhibit the binding of Vif to CBFβ. Homology modeling analysis demonstrated the binding advantages of VMP-63 and VMP-108 with CBFβ over their corresponding wild-type peptides. However, only VMP-108 effectively restricted long-term HIV-1 replication and protected A3 functions in non-permissive T lymphocytes. Our findings suggest that competitive Vif-derived peptides targeting the Vif-CBFβ interaction are promising for the development of novel therapeutic strategies for acquired immune deficiency syndrome.
人类免疫缺陷病毒1型（HIV-1）辅助蛋白Vif的主要功能之一是通过招募Cullin5-ElonginB/C-CBFβ E3泛素连接酶复合物来诱导载脂蛋白B mRNA编辑酶催化多肽样3（APOBEC3，A3）家族蛋白的降解，以促进病毒复制。因此，Vif与E3复合物蛋白之间的相互作用是开发新型抗HIV-1药物的有前景的靶点。在此，基于通过酵母表面展示平台筛选出的对CBFβ具有更高亲和力的Vif突变体序列，设计了针对Vif-CBFβ相互作用的肽段。我们鉴定出两种肽段VMP-63和VMP-108，它们可以降低从A3G阳性细胞产生的HIV-1的感染性，IC50值分别为49.4 μM和55.1 μM。它们保护HEK293T细胞内的A3G不被Vif介导的降解，从而增加A3G包装到子代病毒颗粒中的量。这些肽段添加到HEK293T细胞后可迅速进入细胞，并竞争性抑制Vif与CBFβ的结合。同源建模分析表明，VMP-63和VMP-108与CBFβ的结合优势超过其相应的野生型肽段。然而，只有VMP-108能有效限制HIV-1在非允许性T淋巴细胞中的长期复制并保护A3功能。我们的研究结果表明，靶向Vif-CBFβ相互作用的竞争性Vif衍生肽段有望用于开发获得性免疫缺陷综合征的新型治疗策略。
