Functional Mechanisms of Antibody Inhibition of HIV-1

HIV-1 抗体抑制的功能机制

• 批准号: 7393120
• 负责人: MARSHALL R POSNER
• 金额: $ 39.53万
• 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: 2005-07-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7393120
• 关键词: Address; Animal Model; Antibodies; Antibody Formation; B-Lymphocytes; Binding; Biological; Biological Assay; Cell physiology; Cells; Cellular Immunity; Chemical Vaccines; Complement; Complement Fixation Tests; Dendritic Cells; Deposition; Disease; Epitopes; Functional disorder; Goals; HIV; HIV Envelope Protein gp120; HIV-1; Homo; Immune System Diseases; Immune response; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin Constant Region; Improve Access; In Vitro; Individual; Infection; Infection Control; Marshal; Measures; Mediating; Methods; Modeling; Neutralization Tests; Numbers; Outcome; Prevention; Primates; Process; Research Personnel; Research Proposals; Structure; Surface; Testing; Therapeutic; Vaccination; Vaccines; Viral; Virion; Virus; Virus Diseases; antibody-dependent cell cytotoxicity; base; human monoclonal antibodies; improved; in vivo; neutralizing antibody; neutrophil; nonhuman primate; prevent; programs; response; sample fixation; transmission process

Treatment with neutralizing antibodies is the only therapy that consistently prevents HIV-1 infection in primate models. A limited number of viral envelope regions are important for neutralization and access to conserved regions is camouflaged or restricted. Antibodies which neutralize robustly have unusual physical structures. Thus, the most potent neutralizing antibodies are rarely made during natural infection and are not elicited by vaccination. Antibodies can contribute to control of irfections by mechanisms other then 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 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 functional activities in addition to neutralization that can prevent or enhance HIV-1 infection; antibodies can be modified to improve the outcomes of these processes; and (2) 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 modified antibodies will be tested in these assays for anti-HIV activity and ADCC. Isotype-switched antibodies will 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. Single chain antibodies will be constructed from selected neutralizing antibodies to improve access to neutralizing epitopes.Homo-and hetro-multimers of antibodies will be constructed to study and improve antibody function. 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.

使用中和抗体治疗是唯一能够在灵长类动物模型中持续预防 HIV-1 感染的疗法。有限数量的病毒包膜区域对于中和很重要，并且对保守区域的访问被伪装或限制。强力中和的抗体具有不寻常的物理结构。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。抗体可以通过病毒中和测定所测量的中和以外的机制来控制感染。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，还可以介导多种功能活动；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、中和作用、结合广度和可用性来选择抗体进行研究。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 细胞对调理病毒的传播以及 B 细胞功能。具有补体相关作用的抗体将被修饰以消除补体固定和 修饰抗体将在这些测定中测试抗 HIV 活性和 ADCC。将产生同型转换抗体，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。将从选定的中和抗体构建单链抗体，以改善中和表位的获取。将构建抗体的同源和异源多聚体以研究和改善抗体功能。将测试构建体的病毒粒子 结合、动态病毒粒子结合、中和和抑制病毒感染、复制和传播，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。

项目成果

Neutralization of HIV by milk expressed antibody.

通过乳汁表达的抗体中和 HIV。

• DOI: 10.1097/qai.0b013e318271c450
• 发表时间: 2013
• 期刊: Journal of acquired immune deficiency syndromes (1999)
• 作者: Yu,Xiaocong;Pollock,Daniel;Duval,Mark;Lewis,Christopher;Joseph,Kristin;Meade,Harry;Cavacini,Lisa
• 通讯作者: Cavacini,Lisa

Impact of IgA constant domain on HIV-1 neutralizing function of monoclonal antibody F425A1g8.

IgA 恒定结构域对单克隆抗体 F425A1g8 的 HIV-1 中和功能的影响。

• DOI: 10.4049/jimmunol.1201469
• 发表时间: 2013
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Yu,Xiaocong;Duval,Mark;Lewis,Christopher;Gawron,MelissaA;Wang,Rijian;Posner,MarshallR;Cavacini,LisaA
• 通讯作者: Cavacini,LisaA