Tan Yue, Tong Pei, Wang Junyi, Zhao Lei, Li Jing, Yu Yang, Chen Ying-Hua, Wang Ji
Laboratory of Immunology, School of Life Sciences, Beijing Key Laboratory for Protein Therapeutics, Protein Science Laboratory of the Ministry of Education, Tsinghua University, Beijing, China.
The Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology of Ministry of Education, Department of Chemistry, Tsinghua University, Beijing, China.
Front Immunol. 2017 Apr 24;8:478. doi: 10.3389/fimmu.2017.00478. eCollection 2017.
The initial infection and transmission of HIV-1 requires C-C chemokine receptor type 5 (CCR5). Here, we report that the membrane-proximal region (MPR, aa 22-38) of CCR5 participates in the infection of HIV-1. First, MPR-specific antibodies elicited in mice dose-dependently inhibited the infection of CCR5-tropic HIV-1. Second, substituting MPR with the same region from other co-receptors significantly impaired HIV-1 infection, while the key residues identified by alanine scanning mutagenesis formed an exposed leucine zipper-like structure. Moreover, a peptide derived from MPR could block the infection of a number of HIV-1 strains only before the formation of gp41 six-helix bundle, coincide with the early interaction between CCR5 and the gp120 protein during HIV-1 infection. These promising results ensured the potential of this previously uncharacterized domain as a starting point for the development of antiviral drugs, blocking antibodies, and HIV vaccines.
HIV-1的初始感染和传播需要C-C趋化因子受体5型（CCR5）。在此，我们报告CCR5的膜近端区域（MPR，氨基酸22 - 38）参与HIV-1的感染。首先，在小鼠中诱导产生的MPR特异性抗体以剂量依赖方式抑制CCR5嗜性HIV-1的感染。其次，用其他共受体的相同区域替换MPR会显著损害HIV-1感染，而通过丙氨酸扫描诱变鉴定的关键残基形成了一个暴露的亮氨酸拉链样结构。此外，源自MPR的肽仅在gp41六螺旋束形成之前就能阻断多种HIV-1毒株的感染，这与HIV-1感染期间CCR5与gp120蛋白的早期相互作用一致。这些有前景的结果确保了这个以前未被表征的结构域作为开发抗病毒药物、阻断抗体和HIV疫苗起点的潜力。
