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（由申请人提供）：尽管婴儿占世界人口的不到2%，但每年仍有超过200，000名婴儿感染HIV-1，占全球HIV-1传播的1/8。虽然产妇抗逆转录病毒治疗可以大大减少母婴传播，但即使是最有效的治疗方案也无法消除传播，而且其影响因产妇坚持、获得和监测不良而减弱。最近，在怀孕期间添加第三种抗逆转录病毒药物将围产期HIV-1传播降低到<0.5%，但以婴儿的早产率和死亡率较高为代价，强调需要额外和更安全的策略来消除儿科HIV-1。开发免疫干预措施以消除垂直HIV-1传播将需要定义母体HIV-1 Env特异性抗体的保护特性，这些抗体在出生前和通过母乳喂养被动转移给婴儿。最近，我们使用来自妇女和婴儿传播研究的样本，确定了预测母婴传播风险降低的常见母体抗体应答（WITS，n = 248），一组在ARV前时代入组的美国HIV-1感染母婴对：1）针对Env可变环3（V3）的IgG应答，2）CD 4结合位点特异性抗体应答，和3）进化枝匹配的1级HIV-1变体的中和。潜在地解释了这些确定的母体免疫相关性背后的机制，我们证明了母体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，尽管对异源2级难以中和的病毒没有活性。因此，我们假设，通常引发的非广泛中和抗体（例如针对V3环和CD 4结合位点的抗体）的自体中和是针对MTCT的保护的机械免疫相关性，并且可以通过母体Env免疫引发。在这项研究中，我们将根据我们确定的MTCT风险相关性，探索通过常见的抗体进行自体中和，作为预防MTCT的机制。我们将确定自体中和敏感性是否区分婴儿传播的变体与母体非传播的变体（目标1），绘制定义婴儿传播病毒的中和敏感性的Env区域和氨基酸残基（目标2），并确定在历史性临床试验中，在HIV感染的孕妇中通过异源Env免疫是否可以增强自体中和反应（Aim 3）。我们的研究结果将确定自体中和是否是一种预防MTCT的机制，以及疫苗策略是否可以引起免疫应答。这项工作将为设计和评估消除儿童HIV-1流行所必需的HIV-1免疫策略制定指导原则。