Functional Mechanisms of Antibody Inhibition of HIV-1

HIV-1 抗体抑制的功能机制

• 批准号: 7023524
• 负责人: MARSHALL R POSNER
• 金额: $ 6.31万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7023524
• 关键词: HIV infections; antigen antibody reaction; antiviral antibody; clinical research; human immunodeficiency virus 1; human subject; neutralizing antibody

The administration of neutralizing antibodies before or immediately after HIV-1 challenge is the only identified therapy that consistently prevents infection in primate models of HIV-1. Only a limited number of viral envelope regions are important for viral neutralization, access to the most conserved regions is camouflaged or restricted on the native virion, and antibodies which neutralize will have very unusual physical structure. Thus, the most potent neutralizing antibodies are rarely made during natural infection and are not elicited by vaccination. Antibodies can also contribute to control of infections by mechanisms that do not require neutralization as measured by viral neutralization assays. Antibodies may even promote infection when mechanisms, such as complement deposition, contribute to viral binding and spread or immune dysfunction. We propose, given the structural constraints of the virus and the biological limitations of the humoral immune response, that a better understanding of the full potential of antibodies to prevent viral infection is needed. We propose the following two hypotheses (1) Antibodies can mediate a variety of specific functional activities in addition to neutralization that can prevent or enhance HIV-1 infection; moreover, antibodies can be modified to improve the outcomes of these processes; and (2) that neutralizing antibodies can be molecularly modified to improve neutralization. Antibodies have been selected for study based on epitope, neutralization breadth of binding and availability. Antibodies will be tested for complement-mediated enhancement of infection, neutralization in the presence of complement, transmission of opsonized virus by dendritic cells and B cells and B cell function. Antibodies with complement related effects will be modified to eliminate complement fixation and molecularly modified antibodies will be tested in these assays with controls for anti-HIV activity and ADCC. Isotype switched antibodies will also be generated, including IgA antibodies to study function. The isotype switched constructs will be tested for neutralization, virion binding, ADCC, neutrophil mediated viral destruction, prevention of transmission of HIV in trans, and prevention of trancytosis. To improve neutralization, single chain antibodies will be constructed for selected neutralizing antibodies to improve access to neutralizing epitopes and homo and hetero-multimers of antibodies will be constructed to study and improve antibody function. All neutralization constructs will be tested for virion binding, dynamic virion binding, neutralization, and inhibition of viral infection, replication and transmission to correlate binding, function, and structure. Long-term objectives will be to select constructs from in vitro testing for further testing in non-human primate models of prevention and therapeutics.

在 HIV-1 攻击之前或之后立即施用中和抗体是唯一已确定的能够持续预防 HIV-1 灵长类动物模型感染的疗法。只有有限数量的病毒包膜区域对于病毒中和很重要，对最保守区域的访问被伪装或限制在天然病毒粒子上，并且中和的抗体将具有非常不寻常的物理结构。因此，最有效的中和抗体很少在自然感染过程中产生，也不是通过疫苗接种引起的。 抗体还可以通过不需要中和的机制来控制感染，如病毒中和测定所测量的。当补体沉积等机制导致病毒结合和传播或免疫功能障碍时，抗体甚至可能促进感染。我们建议，考虑到病毒的结构限制和体液免疫反应的生物学限制，需要更好地了解抗体预防病毒感染的全部潜力。我们提出以下两个假设：（1）抗体除了可以预防或增强HIV-1感染的中和作用外，还可以介导多种特定的功能活动；此外，可以修改抗体以改善这些过程的结果； (2)可以对中和抗体进行分子修饰以改善中和作用。根据表位、结合中和广度和可用性选择抗体进行研究。将测试抗体的补体介导的感染增强、补体存在下的中和、树突状细胞和 B 细胞传播调理病毒以及 B 细胞功能。抗体具有 补体相关效应将被修改以消除补体固定，分子修饰的抗体将在这些测定中进行测试，并对照抗 HIV 活性和 ADCC。还将生成同型转换抗体，包括用于研究功能的 IgA 抗体。将测试同种型转换构建体的中和、病毒颗粒结合、ADCC、中性粒细胞介导的病毒破坏、预防HIV反式传播以及预防转胞吞作用。为了改善中和，将为选定的中和抗体构建单链抗体，以改善中和表位的接近，并且将构建抗体的同源和异源多聚体以研究和改善抗体功能。所有中和构建体都将进行病毒粒子结合、动态病毒粒子结合、中和以及病毒感染、复制和传播的抑制测试，以关联结合、功能和结构。长期目标是从体外测试中选择构建体，以便在非人类灵长类动物的预防和治疗模型中进行进一步测试。