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: 9294963
• 负责人: FENG GAO
• 金额: $ 60.87万
• 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/9294963
• 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; Chronic; 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; Immunologic Factors; Individual; Infant; Infection; Interruption; Intervention; Lead; Maps; Maternal antibody; Measures; Mediating; Monitor; Monoclonal Antibodies; Mothers; Mutate; Mutation; Passive Transfer of Immunity; Perinatal; Pharmaceutical Preparations; Plasma; Polysaccharides; Population; Pregnancy; Pregnant Women; Premature Infant; Prevention strategy; Property; Prophylactic treatment; Regimen; Resistance; Resources; Risk; Role; Sampling; Sequence Analysis; Specificity; Vaccinated; Vaccination; Vaccines; Variant; Vertical Disease Transmission; Viral; Virus; Woman; Work; base; clinical translation; cohort; design; immunological intervention; maternal vaccination; neutralizing antibody; neutralizing monoclonal antibodies; pediatric human immunodeficiency virus; predicting response; 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比例不到 2%，但每年仍有超过 200,000 名婴儿继续感染 HIV-1，占全球 HIV-1 传播的 1/8。尽管孕产妇抗逆转录病毒 (ARV) 治疗可以显着减少母婴传播，但即使是最有效的治疗方案也无法消除传播，而且其影响因孕产妇依从性、获取和监测不佳而减弱。最近，在怀孕期间添加第三种抗逆转录病毒药物可将围产期 HIV-1 传播率降低至 <0.5%，但代价是婴儿的早产率和死亡率较高，这凸显了需要采取额外且更安全的策略来消除儿科 HIV-1。制定免疫干预措施以消除 HIV-1 垂直传播需要确定母体 HIV-1 包膜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。我们最近使用来自妇女和婴儿传播研究（WITS，n = 248）的样本确定了预测母婴传播风险降低的常见母体抗体反应，该研究是抗逆转录病毒治疗前时代登记的一组美国 HIV-1 感染母婴对：1) 针对 Env 可变环 3 (V3) 的 IgG 反应，2) CD4 结合位点特异性抗体反应，以及 3) 中和进化枝匹配的 1 级 HIV-1 变体。我们证明，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，尽管对难以中和的异源 2 级病毒没有活性，这可能解释了这些已确定的母体免疫相关因素背后的机制。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 CD4 结合位点的抗体）的自体中和是针对 MTCT 保护的机械免疫相关性，并且可以通过母体 Env 免疫引起。在这笔资助中，我们将根据我们确定的 MTCT 风险相关性，探讨常见引发的抗体的自体中和作用，作为预防 MTCT 的机制。我们将确定自体中和敏感性是否能够区分婴儿传播的变异与母体非传播的变异（目标 1），绘制定义婴儿传播病毒的中和敏感性的 Env 区域和氨基酸残基图谱（目标 2），并确定在历史临床试验中 HIV 感染孕妇中的异源 Env 免疫是否可以增强自体中和反应（目标 3）。我们的结果将确定自体中和是否是预防母婴传播的一种机制以及疫苗策略可以引发的反应。这项工作将为设计和评估 HIV-1 免疫策略制定指导原则，这对于消除儿童 HIV-1 流行至关重要。