INVOLVEMENT OF PROTEOGLYCANS AND POLYANIONIC POLYSACCHARIDES IN HIV INFECTION

我们的实验室正在继续研究这一疾病的分子机制。 多阴离子化合物的抗病毒作用及细胞表面的作用 蛋白多糖在介导HIV-1感染中的作用。我们的结果揭示了 多阴离子多糖对病毒的抑制作用 结合、病毒复制和合胞体的形成是由 与gpl20的V3原理中和结构域的相互作用 靠近CD4结合部位的包膜区域。我们还确定了一个 细胞表面硫酸化多糖--硫酸乙酰肝素蛋白多糖 T细胞表面共同发挥作用的新的HIV结合部位 用CD4来调节HIV的进入。我们已经通过生物化学鉴定出 人类免疫缺陷病毒易感T细胞系和HAVs细胞中蛋白多糖的合成 用肝素酶和酶处理T细胞系证实 通过抑制硫酸乙酰肝素的糖胺多聚糖硫酸盐化 是HIV-1感染所必需的。我们已经量化了病毒的直接结合 并发现用肝素酶处理细胞 抑制HIV-1与T细胞表面的结合。外源HS添加到 培养物抑制病毒感染的方式类似于葡聚糖 硫酸盐，进一步支持HS在HIV-1结合中的功能作用。 这些结果为细胞表面的参与提供了直接证据 硫酸乙酰肝素蛋白多糖在HIV细胞附着和病毒侵入中的作用。 对这个新单元格输入站点的描述可能会考虑到 抗病毒治疗的其他模式。

Our laboratory has continued investigating the molecular mechanism of the antiviral effects of polyanionic compounds and the role of cell surface proteoglycans in mediating HIV-1 infection. Our results have revealed that the inhibitory effects of polyanionic polysaccharides on viral binding, viral replication and syncytia formation are mediated by interactions with the V3 principle neutralizing domain of gpl20 and with envelope regions near the CD4 binding site. We have also identified a cell surface sulfated polysaccharide, heparan sulfate proteoglycan, as a novel HIV binding site on the T-cell surface which functions together with CD4 to mediate HIV entry. We have biochemically identified proteoglycan synthesis in HIV susceptible T-cell lines and have demonstrated by enzymatic treatment of T-cell lines with heparitinase and by inhibition of glycosaminoglycan sulfation that heparan sulfate is required for HIV-1 infection. We have quantitated direct virus binding to cells and have found that treatment of cells with heparitinase inhibits HIV-1 binding to the T-cell surface. Exogenous HS added to cultures inhibited virus infection in a manner analogous to dextran sulfate, further supporting a functional role for HS in HIV-1 binding. These results provide direct evidence for participation of cell surface heparan sulfate proteoglycans in HIV-cell attachment and virus entry. The description of this new cell entry site potentially should allow for additional modes of antiviral therapies.