Residues L55 and W69 of Tva Mediate Entry of Subgroup A Avian Leukosis Virus

文献类型： 外文期刊

第一作者： Chen, Yuntong

作者： Chen, Yuntong;Wang, Suyan;Li, Xinyi;Yu, Mengmeng;Liu, Peng;Meng, Lingzhai;Guo, Ru;Feng, Xiaoyan;Liu, Aijing;Qi, Xiaole;Li, Kai;Gao, Li;Pan, Qing;Zhang, Yanping;Liu, Changjun;Cui, Hongyu;Wang, Xiaomei;Gao, Yulong;Wang, Xiaomei

作者机构：

关键词： receptors; subgroup A avian leukosis virus; virus entry

期刊名称：JOURNAL OF VIROLOGY （ 影响因子：6.549； 五年影响因子：5.78 ）

ISSN： 0022-538X

年卷期： 2022 年 96 卷 18 期

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收录情况： SCI

摘要： Retroviruses bind to cellular receptors through their envelope proteins, which is a crucial step in infection. While most retroviruses require two receptors for entry, ALV-A requires only one. The receptor of the subgroup A avian leukosis virus (ALV-A) in chicken is Tva, which is the homologous protein of human CD320 (huCD320), contains a low-density lipoprotein (LDL-A) module and is involved in the uptake of transcobalamin bound vitamin B-12/cobalamin (Cbl). To map the functional determinants of Tva responsible for ALV-A receptor activity, a series of chimeric receptors were created by swapping the LDL-A module fragments between huCD320 and Tva. These chimeric receptors were then used for virus entry and binding assays to map the minimal ALV-A functional domain of Tva. The results showed that Tva residues 49 to 71 constituted the minimal functional domain that directly interacted with the ALV-A gp85 protein to mediate ALV-A entry. Single-residue substitution analysis revealed that L55 and W69, which were spatially adjacent on the surface of the Tva structure, were key residues that mediate ALV-A entry. Structural alignment results indicated that L55 and W69 substitutions did not affect the Tva protein structure but abolished the interaction force between Tva and gp85. Furthermore, substituting the corresponding residues of huCD320 with L55 and W69 of Tva converted huCD320 into a functional receptor of ALV-A. Importantly, soluble huCD320 harboring Tva L55 and W69 blocked ALV-A entry. Finally, we constructed a Tva gene-edited cell line with L55R and W69L substitutions that could fully resist ALV-A entry, while Cbl uptake was not affected. Collectively, our findings suggested that amino acids L55 and W69 of Tva were key for mediating virus entry. IMPORTANCE Retroviruses bind to cellular receptors through their envelope proteins, which is a crucial step in infection. While most retroviruses require two receptors for entry, ALV-A requires only one. Various Tva alleles conferring resistance to ALV-A, including Tva(r1) (C40W substitution), Tva(r2) (frame-shifting four-nucleotide insertion), Tva(r3), Tva(r4), Tva(r5), and Tva(r6) (deletion in the first intron), are known. However, the detailed entry mechanism of ALV-A in chickens remains to be explored. We demonstrated that Tva residues L55 and W69 were key for ALV-A entry and were important for correct interaction with ALV-A gp85. Soluble Tva and huCD320 harboring the Tva residues L55 and W69 effectively blocked ALV-A infection. Additionally, we constructed gene-edited cell lines targeting these two amino acids, which completely restricted ALV-A entry without affecting Cbl uptake. These findings contribute to a better understanding of the infection mechanism of ALV-A and provided novel insights into the prevention and control of ALV-A.

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