Functional Mechanisms of Antibody Inhibition of HIV-1

HIV-1 抗体抑制的功能机制

• 批准号: 7386965
• 负责人: MARSHALL R POSNER
• 金额: $ 17万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7386965
• 关键词: Anti-Retroviral Agents; Antibodies; Antibody Activation; Antibody-mediated protection; Antigens; B-Lymphocytes; Binding; Chinese Hamster Ovary Cell; Class; Engineering; Epitopes; Glycoproteins; HIV; HIV Infections; HIV-1; Immune system; Immunodominant Epitopes; Immunoglobulin G; Individual; Infection prevention; Lectin; Low Prevalence; Measures; Modeling; Monoclonal Antibodies; Neutralization Tests; Pattern; Peptides; Post-Translational Protein Processing; Series; Serum; Structure; Vaccination; Viral; Viral Antibodies; Viral Load result; Virus; base; glycosylation; human monoclonal antibodies; immunogenic; neutralizing antibody; nonhuman primate; response; transmission process

DESCRIPTION (provided by applicant): The vast majority of antibodies produced during HIV infection or as a consequence of vaccination fail to neutralize primary isolate virus. This is not surprising given (1) the structure of the HIV-1 envelope glycoprotein - most of the neutralizing epitopes are obscured or only transiently exposed; and (2) the fact that the immune system cannot differentiate between merely immunogenic and critically protective epitopes. The majority of highly effective neutralizing human monoclonal antibodies for specific epitopes have relatively unique or unusual structural features. It has also been shown that passive administration of some anti- IV neutralizing antibodies, usually in combination, can prevent infection or transmission in nonhuman primate models and have a prolonged impact on viral load when used in combination with anti-retroviral therapy in non-human primates. One of the more immunogenic regions of the HIV-1 envelope glycoprotein is the immunodominant, ectodomain of gp41. Antibodies to this region are prevalent in HIV-1 infected individuals; however, monoclonal antibodies to the immunodominant (ID) ectodomain are not associated with HIV-1 neutralization. We have now shown that post-translational modification in the glycosylation of one non-neutralizing anti-gp41 ID antibody, F240, conferred robust neutralizing activity on the antibody. We believe this may be a more generalized mechanism of activation for antibodies to this epitope and that understanding the contribution of the specific post-translational modifications of this class of antibodies will make it possible to identify mechanisms to direct the post-translational modification of antibodies in B cells of immunized individuals. To explore this hypothesis, we propose to identify other human monoclonal antibodies to gp41 ID epitope which neutralize when glycosylated in CHO cells. We hypothesize that, similar to that observed for F240, differential glycosylation of other human monoclonal antibodies (HMAb) to the gp41 ID epitope, but not necessarily all, will result in HIV neutralization. Furthermore, serum antibodies to the immunodominant domain will be characterized as to glycosylation patterns and differentially glycosylated antibodies purified to test for neutralization. We hypothesize that differential glycosylation will be observed for serum antibodies with a low prevalence of glycosylation similar to that seen for CHO expressed F240 antibody and which may be used to predict effective serum based antibody mediated protection.

描述（由申请人提供）：在 HIV 感染期间或由于疫苗接种而产生的绝大多数抗体无法中和初级分离病毒。这并不奇怪，因为 (1) HIV-1 包膜糖蛋白的结构 - 大多数中和表位被遮盖或仅短暂暴露； (2)事实上，免疫系统无法区分单纯的免疫原性表位和关键保护性表位。大多数针对特定表位的高效中和人单克隆抗体具有相对独特或不寻常的结构特征。还表明，被动施用一些抗 IV 中和抗体（通常联合使用）可以预防非人灵长类动物模型中的感染或传播，并且当与非人灵长类动物模型中的抗逆转录病毒治疗联合使用时，可以对病毒载量产生长期影响。灵长类动物。 HIV-1 包膜糖蛋白的免疫原性更强的区域之一是 gp41 的免疫显性区外域。该区域的抗体在 HIV-1 感染者中普遍存在；然而，免疫显性 (ID) 胞外域的单克隆抗体与 HIV-1 中和无关。我们现在已经证明，一种非中和性抗 gp41 ID 抗体 F240 的糖基化的翻译后修饰赋予了该抗体强大的中和活性。我们相信，这可能是针对该表位的抗体的更普遍的激活机制，并且了解此类抗体的特定翻译后修饰的贡献将使得有可能确定指导抗体翻译后修饰的机制。免疫个体的 B 细胞。为了探索这一假设，我们建议鉴定其他针对 gp41 ID 表位的人单克隆抗体，这些抗体在 CHO 细胞中糖基化时会发生中和。我们假设，与在 F240 中观察到的情况类似，其他人单克隆抗体 (HMAb) 对 gp41 ID 表位（但不一定是全部）的差异糖基化将导致 HIV 中和。此外，免疫显性结构域的血清抗体将被表征为糖基化模式和纯化的差异糖基化抗体以测试中和。我们假设血清抗体会观察到差异糖基化，其糖基化发生率较低，与 CHO 表达的 F240 抗体相似，这可用于预测基于血清的有效抗体介导的保护。