ANTI CD4 BASED THERAPIES FOR HIV INFECTION

某些针对CD4的单抗可以 在体外有效地阻断HIV-1的复制。探索由CD_4引导的 被动免疫疗法在艾滋病病毒防治中的应用 感染，我们之前检查了一个生物活性 非耗竭的CD4特异性小鼠单抗，mu5A8。此单抗，专用于 CD4结构域2在gp120/CD4结合后阻断HIV-1复制 一步。当给正常恒河猴注射时，所有的CD4+靶 细胞被抗体包被，但没有细胞清除或可测量的 出现免疫抑制。然而，强烈的抗鼠Ig反应 在所有猴子中迅速发育。在本研究中，我们报告了一种 成功人源化形式的mu5A8(Hu5A8)，保留与 兼具人和猴的CD4和抗艾滋病病毒活性。什么时候 给正常恒河猴静脉注射H5A8结合 所有靶向CD4+细胞均未耗尽，并显示出明显的 比mu5A8的等离子体半衰期更长。然而，一种抗H5A8病毒 主要针对V区决定因素的反应 最终在大多数动物身上出现在两到四周内。然而， 当给慢性感染的恒河猴注射hu5a8时 用猴免疫缺陷病毒，抗Hu5A8 未检测到抗体。HU5A8在中国的重复使用 这些动物导致持续的血浆水平和CD4+细胞 用人源化抗体包被六周。这些研究 论证慢性给药的可行性 单抗作为治疗或预防HIV-1感染的潜在手段。

Certain monoclonal antibodies (mAb) directed against CD4 can efficiently block HIV-1 replication in vitro. to explore CD4-directed passive immunotherapy for prevention or treatment of AIDS-virus infection, we previously examined the biological activity of a nondepleting CD4-specific murine mAb, mu5A8. This mAb, specific for domain 2 of CD4 blocks HIV-1 replication at a post-gp120/CD4 binding step. When administered to normal rhesus monkeys, all CD4+ target cells were coated with antibody, yet no cell clearance or measurable immunosuppression occurred. However, strong anti-mouse Ig responses rapidly developed in all monkeys. In the present study, we report a successfully humanized form of mu5A8 (hu5A8) that retains binding to both human and monkey CD4 and anti-AIDS virus activity. When administered intravenously to normal rhesus monkeys, hu5A8 bound to all target CD4+ cells without depletion and showed a significantly longer plasma half-life than mu5A8. Nevertheless, an anti-hu5A8 response directed predominantly against V region determinants did eventually appear within two to four weeks in most animals. However, when hu5A8 was administered to rhesus monkeys chronically infected with the simian immunodeficiency virus of macaques, anti-hu5A8 antibodies were not detected. Repeated administration of hu5A8 in these animals resulted in sustained plasma levels and CD4+ cell coating with humanized antibody for six weeks. These studies demonstrate the feasibility of chronic administration of CD4-specific mAb as a potential means of treating or preventing HIV-1 infection.