Role of neutralizing antibodies in HIV-1-infected and vaccinated mothers in MTCT

中和抗体在 HIV-1 感染和接种疫苗的母亲中在 MTCT 中的作用

• 批准号: 9064432
• 负责人: FENG GAO
• 金额: $ 62.35万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9064432
• 关键词: Accounting; Adherence; Amino Acids; Anti-Retroviral Agents; Antibodies; Antibody Formation; Antibody Response; Antibody-mediated protection; Area; Autologous; B-Lymphocytes; Binding Sites; Birth; Breast Feeding; Cell Separation; Cessation of life; Childhood; Clinical; Clinical Research; Clinical Trials; Death Rate; Dependence; Development; Enrollment; Epidemic; Epitopes; Evaluation; Generations; Genome; Goals; Grant; HIV; HIV-1; Immune; Immune response; Immunization; Immunoglobulin G; Immunologics; Individual; Infant; Infection; Intervention; Lead; Maps; Maternal antibody; Measures; Mediating; Monitor; Monoclonal Antibodies; Mothers; Mutate; Mutation; Perinatal; Pharmaceutical Preparations; Plasma; Polysaccharides; Population; Pregnancy; Pregnant Women; Prevention strategy; Property; Prophylactic treatment; Regimen; Resistance; Resources; Risk; Role; Sampling; Sequence Analysis; Specificity; Translations; Vaccinated; Vaccination; Vaccines; Variant; Vertical Disease Transmission; Viral; Virus; Woman; Work; base; cohort; design; neutralizing antibody; neutralizing monoclonal antibodies; premature; public health relevance; response; transmission process; vaccine response; vaccine trial

 DESCRIPTION (provided by applicant): More than 200,000 infants continue to become infected with HIV-1 annually, accounting for 1/8th of the worldwide HIV-1 transmission, despite infants representing <2% of the world's population. Although maternal antiretroviral (ARV) treatment can dramatically reduce MTCT, even the most potent regimens have been unable to eliminate transmission, and their impact is weakened by poor maternal adherence, access, and monitoring. Recently, the addition of a 3rd ARV during pregnancy reduced peripartum HIV-1 transmission to <0.5%, yet came at the expense of a higher prematurity and death rate in infants, underscoring the need for additional and safer strategies to eliminate pediatric HIV-1. Developing immunologic interventions to eliminate vertical HIV-1 transmission will require defining the protective properties of maternal HIV-1 Env-specific antibodies that are passively transferred to the infant prior to birth and via breastfeeding. We recently identified commonly-elicited maternal antibody responses that predict reduced risk of MTCT using samples from the Women and Infants Transmission Study (WITS, n = 248), a cohort of U.S. HIV-1-infected mother-infant pairs enrolled in the pre-ARV era: 1) IgG responses directed against the Env variable loop 3 (V3), 2) CD4 binding site-specific antibody responses, and 3) neutralization of clade-matched tier 1 HIV-1 variants. Potentially explaining the mechanism behind these identified maternal immune correlates, we demonstrated that maternal Env V3-specific monoclonal antibodies can neutralize concurrently circulating autologous virus variants, despite having no activity against heterologous tier 2, difficult-to-neutralize viruses. Thus, we hypothesize that autologous neutralization by commonly-elicited, non-broadly neutralizing antibodies, such as those directed against the V3 loop and CD4 binding site, are mechanistic immune correlates of protection against MTCT and can be elicited by maternal Env immunization. In this grant, we will probe autologous neutralization by commonly-elicited Abs as a mechanism of protection against MTCT, based on our identified correlates of MTCT risk. We will determine whether autologous neutralization sensitivity distinguishes infant transmitted variants from maternal non- transmitted variants (Aim 1), map the Env regions and amino acid residues that define the neutralization sensitivity of infant transmitted viruses (Aim 2), and determine whether autologous neutralization responses can be enhanced by heterologous Env immunization among HIV-infected pregnant women in a historical clinical trial (Aim 3). Our results will establish whether autologous neutralization is a mechanism of protection against MTCT and a response that can be elicited by vaccine strategies. This work will establish guiding principles for design and evaluation of HIV-1 immunization strategies that will be necessary to eliminate the pediatric HIV-1 epidemic.

 描述（由适用提供）：超过200,000名婴儿每年继续感染HIV-1，占全球HIV-1传播的1/8，占全球人口<2％的多皮特婴儿。尽管生物抗逆转录病毒（ARV）治疗可以大大降低MTCT，但即使是最潜在的方案也无法消除传播，并且由于较差的物质，获取和监测而削弱了其影响。最近，在怀孕期间增加第三ARV将外周HIV-1传播降低到<0.5％，但以牺牲婴儿的早产和死亡率为代价，强调需要采取其他安全策略来消除小儿HIV-1。开发免疫学干预措施以消除垂直的HIV-1传播将需要定义母体HIV-1 ENV特异性抗体的受保护特性，这些抗体在出生前和通过母乳喂养在出生前被动转移到婴儿。我们最近确定了使用妇女和婴儿传播研究的样本（WITS，n = 248）的样本（美国HIV-1感染的母亲感染的群体组成的群体，预测MTCT的风险降低），这是MTCT的风险降低，这是ARV前的ARV ERA中招募的摄入的igg响应，IGG响应于Envibib 3（V3（V3），v3（V3），2），2），2）进化枝匹配层1 HIV-1变体的谈判。潜在地解释了这些已鉴定出的遗物免疫物背后的机制，我们证明了雄性Env V3特异性单克隆抗体可以中和同时循环的自体病毒变体，而泛岩没有针对异源层次2的活性，难以中性地中性病毒。这是我们假设通过普遍吸收的，非大通中和抗体（例如针对V3环和CD4结合位点的）的自体神经化是对MTCT的机械免疫物质的，并且可以被物质在内的Envental Envental Insunosunosunosunosunosunosunosppression引起。在这笔赠款中，我们将基于我们确定的MTCT风险相关性，通过普遍释放的ABS作为对MTCT的保护机制来探测自体神经仿真。我们将确定自体神经仿真敏感性是否将婴儿传播的变异与母体非传播变异区分开（目标1），映射环境区域和氨基酸保留的定义婴儿传播病毒的神经系统敏感性（AIM 2）（AIM 2）（AIM 2）的妇女临床的试验是否可以增强自动性神经植物的临床构成，是否可以增强自动性神经临床的影响。 （目标3）。我们的结果将确定自体神经化是否是对MTCT的保护机制，并且可以通过疫苗策略引起的反应。这项工作将建立指导原则，以设计和评估HIV-1免疫抑制策略，这是消除小儿HIV-1流行的必要条件。