Department of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy.
PLoS One. 2011;6(7):e22081. doi: 10.1371/journal.pone.0022081. Epub 2011 Jul 19.
To penetrate susceptible cells, HIV-1 sequentially interacts with two highly conserved cellular receptors, CD4 and a chemokine receptor like CCR5 or CXCR4. Monoclonal antibodies (MAbs) directed against such receptors are currently under clinical investigation as potential preventive or therapeutic agents. We immunized Balb/c mice with molecular complexes of the native, trimeric HIV-1 envelope (Env) bound to a soluble form of the human CD4 receptor. Sera from immunized mice were found to contain gp120-CD4 complex-enhanced antibodies and showed broad-spectrum HIV-1-inhibitory activity. A proportion of MAbs derived from these mice preferentially recognized complex-enhanced epitopes. In particular, a CD4-specific MAb designated DB81 (IgG1Κ) was found to preferentially bind to a complex-enhanced epitope on the D2 domain of human CD4. MAb DB81 also recognized chimpanzee CD4, but not baboon or macaque CD4, which exhibit sequence divergence in the D2 domain. Functionally, MAb DB81 displayed broad HIV-1-inhibitory activity, but it did not exert suppressive effects on T-cell activation in vitro. The variable regions of the heavy and light chains of MAb DB81 were sequenced. Due to its broad-spectrum anti-HIV-1 activity and lack of immunosuppressive effects, a humanized derivative of MAb DB81 could provide a useful complement to current preventive or therapeutic strategies against HIV-1.
为了穿透易感细胞，HIV-1 依次与两种高度保守的细胞受体相互作用，即 CD4 和趋化因子受体，如 CCR5 或 CXCR4。目前，针对这些受体的单克隆抗体（MAb）正在进行临床研究，作为潜在的预防或治疗药物。我们用与可溶性人 CD4 受体结合的天然三聚体 HIV-1 包膜（Env）的分子复合物免疫 Balb/c 小鼠。发现免疫小鼠的血清中含有 gp120-CD4 复合物增强的抗体，并显示出广谱的 HIV-1 抑制活性。从这些小鼠中衍生的一部分 MAb 优先识别复合物增强的表位。特别是，一种命名为 DB81（IgG1Κ）的 CD4 特异性 MAb 被发现优先结合人 CD4 的 D2 结构域上的复合物增强表位。DB81 MAb 还识别黑猩猩 CD4，但不识别狒狒或猕猴 CD4，因为它们在 D2 结构域中存在序列差异。在功能上，DB81 MAb 显示出广谱的 HIV-1 抑制活性，但它在体外对 T 细胞激活没有抑制作用。DB81 MAb 的重链和轻链的可变区被测序。由于其广谱的抗 HIV-1 活性和缺乏免疫抑制作用，DB81 MAb 的人源化衍生物可以为当前针对 HIV-1 的预防或治疗策略提供有用的补充。
