EXPRESSION AND CHARACTERIZATION OF CD4-IGG(2), A NOVEL HETEROTETRAMER THAT NEUTRALIZES PRIMARY HIV TYPE-1 ISOLATES
EXPRESSION AND CHARACTERIZATION OF CD4-IGG(2), A NOVEL HETEROTETRAMER THAT NEUTRALIZES PRIMARY HIV TYPE-1 ISOLATES
复制标题
DOI：
10.1089/aid.1995.11.533
复制
发表时间：
1995-05-01
影响因子：
1.5
通讯作者：
MADDON, PJ
中科院分区：
文献类型：
--
作者：
ALLAWAY, GP;DAVISBRUNO, KL;MADDON, PJ
CD 4-IgG（2）是包含人IgG（2）的新型融合蛋白，其中重链和轻链的Fv部分已被人CD 4的V1和V2结构域取代。这种四聚体蛋白正在开发作为一种免疫预防剂，以减少感染后的HIV-1暴露的可能性，在设置，如职业或围产期暴露于病毒。CD 4-IgG（2）已在中国仓鼠卵巢细胞中表达，并以完全组装的异源四聚体形式分泌。该蛋白以纳摩尔亲和力结合来自实验室适应株和HIV-1的初级分离株的纯化gp 120。兔药代动力学研究表明，与可溶性CD 4（sCD 4）的15 min相比，CD 4-IgG（2）的血浆终末半衰期大于1天，CD 4-IgG（2）不与U937单核细胞/巨噬细胞表面的Fc受体结合，与掺入IgG Fc部分的分子（1）相比，CD 4-IgG（2）介导抗体依赖性增强感染或HIV-1经胎盘传播等功能的潜力较小。当在无病毒HIV-1包膜糖蛋白介导的细胞融合试验中进行测试时，四聚体CD 4-IgG（2）分子比单体sCD 4或二聚体CD 4-γ 2融合蛋白更有效地抑制合胞体形成，这表明该蛋白将阻断HIV-1的细胞间传播。此外，CD 4-IgG（2）有效地中和了一组实验室适应的HIV-1菌株和原始分离株，包括具有不同嗜性的菌株和从疾病的不同阶段分离的菌株，其浓度应易于在体内达到。
CD4-IgG(2) is a novel fusion protein comprising human IgG(2) in which the Fv portions of both heavy and light chains have been replaced by the V1 and V2 domains of human CD4. This tetrameric protein is being developed as an immunoprophylactic agent to reduce the probability of infection following HIV-1 exposure, in settings such as occupational or perinatal exposure to the virus. CD4-IgG(2) has been expressed in Chinese hamster ovary cells and is secreted as a fully assembled heterotetramer. The protein binds with nanomolar affinity to purified gp120 from both a laboratory-adapted strain and a primary isolate of HIV-1. Pharmacokinetic studies in rabbits demonstrated that CD4-IgG(2) has a plasma terminal half-life greater than 1 day, compared with 15 min for soluble CD4 (sCD4), CD4-IgG(2) does not bind to Fc receptors on the surface of U937 monocyte/macrophage cells, Compared to molecules that incorporate the Fc portion of IgG(1), CD4-IgG(2) has less potential to mediate functions such as antibody-dependent enhancement of infection or transplacental transmission of HIV-1. When tested in a virus-free HIV-1 envelope glycoprotein-mediated cell fusion assay, the tetrameric CD4-IgG(2) molecule inhibited syncytium formation more effectively than monomeric sCD4 or a dimeric CD4-gamma 2 fusion protein, This suggests the protein will block cell-to-cell transmission of HIV-1, Moreover, CD4-IgG(2) effectively neutralized a panel of laboratory-adapted strains and primary isolates of HIV-1, including strains with different tropisms and isolated from different stages of the disease, at concentrations that should be readily achieved in vivo.