Escape of maternal plasma broadly neutralizing antibody as a mechanism of mother to child HIV transmission

母体血浆广泛中和抗体的逃逸是艾滋病毒母婴传播的机制

• 批准号: 10327003
• 负责人: Sallie R. Permar
• 金额: $ 74.42万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10327003
• 关键词: Accounting; Antibodies; Antibody Repertoire; Antiviral Agents; Autologous; B cell repertoire; Birth; Case Study; Cessation of life; Clinical Research; Clinical Trials; Development; Epidemic; Epitopes; Future; Generations; Goals; HIV; HIV Infections; HIV therapy; HIV vaccine; HIV-1; Immune; Immunoglobulin G; Immunologics; Impairment; Infant; Infection; Intervention; Lactation; Maps; Maternal antibody; Measures; Mediating; Monoclonal Antibodies; Mother-to-child HIV transmission; Mothers; Mutation; Plasma; Population; Pregnancy; Pregnant Women; Premature Infant; Prevention strategy; Prophylactic treatment; Regimen; Resistance; Risk; Risk Factors; Role; Route; Safety; Site; Specificity; Testing; Time; Vaccination; Vaccines; Variant; Vertical Disease Transmission; Viral; Virus; Woman; antiretroviral therapy; base; clinical development; cohort; design; genetic signature; high risk infant; infant infection; maternal vaccination; neutralizing antibody; novel; pediatric human immunodeficiency virus; pediatric human immunodeficiency virus infection; placental transfer; predicting response; pressure; prevent; repository; response; risk selection; tool; transmission process; viral transmission; virus envelope

Abstract Over 150,000 HIV-1 infants are infected via mother to child transmission (MTCT) each year, accounting for nearly 10% of the global annual HIV-1 infections. Even implementation of highly effective antiretroviral therapy (ART) cannot prevent up to 5% of HIV-1 infected women from transmitting the virus to their infants. Thus, approaches that synergize with ART will be needed to eliminate MTCT. The most promising interventions in under clinical development to prevent HIV infection includes passive administration or active induction of broadly-neutralizing antibodies (bnAbs). Yet, paradoxically, broad neutralization activity in maternal plasma has been associated with risk of infant transmission, raising concerns about the safety of these approaches in pregnancy. Thus, a better understanding of the role of maternal neutralizing activity and MTCT risk is needed to develop effective bnAb-based interventions, which together with ART can more effectively block MTCT. HIV MTCT is a unique transmission route that occurs in the setting of preexisting antibody raised against autologous viruses. We previously found that transmitted/founder (T/F) viruses in infants were more resistant to neutralization by paired maternal plasma than non-transmitted maternal viruses. Moreover, we established that bnAb activity in maternal plasma can drive the development of circulating viral escape variants that become infant T/F viruses. We hypothesize that multispecificity of maternal plasma bnAb activity is associated with reduced risk of MTCT and autologous virus escape from these functional responses by infant T/F viruses is a risk factor for transmission. Moreover, identifying bnAb escape variants that are fit for transmission is important to designing combination bnAb approaches that can effectively prevent virus transmission. We will use the following three Specific Aims to test our hypotheses: (1) Compare the specificity and polyfunctionality of plasma bnAb activity from transmitting and non-transmitting mothers to assess the role of maternal bnAb activity in vertical virus transmission risk. (2) Determine if infant T/F viruses and circulating viruses of transmitting mothers are more resistant to plasma neutralizing activity compared to that of non-transmitted maternal variants from transmitting and non-transmitting mothers. (3) Define genetic signatures responsible for escape from the maternal Env-specific B cell repertoire among transmitted infant Env variants using a panel of native Env trimer-specific mAbs isolated from transmitting mothers. Defining the specificity and function of pre-existing maternal neutralizing antibodies that can reduce virus escape and impede transmission will be critical to design novel passive and active vaccine approaches that can eliminate HIV transmission from mothers to infants, and is a tool to define the population impact of the future use of bnAb- based prophylaxis on HIV transmission dynamics.

抽象的 每年通过母亲到儿童传播（MTCT）感染超过15万HIV-1婴儿 全球年度HIV-1感染的近10％。甚至实施高效的抗逆转录病毒疗法 （ART）不能阻止多达5％的HIV-1感染妇女将病毒传播给婴儿。因此， 消除MTCT需要与ART协同作用的方法。最有希望的干预措施 在临床发育下以防止艾滋病毒感染包括被动施用或主动诱导 广泛中和抗体（BNABS）。然而，矛盾的是，母体血浆中和中和活性广泛 与婴儿传播的风险有关，引起了人们对这些方法安全性的担忧 怀孕。因此，需要更好地了解母体中和活动的作用和MTCT风险 为了开发有效的基于BNAB的干预措施，与ART一起可以更有效地阻止MTCT。 HIV MTCT是一条独特的传输路线，发生在提出的抗体的环境中 自体病毒。我们先前发现，婴儿传播/创始人（T/F）病毒具有更大的抗性 与非转移母体病毒相比，配对的母体血浆中和。而且，我们建立了 母体血浆中的BNAB活性可以推动循环病毒逃生变种的发展 成为婴儿T/F病毒。我们假设母体等离子体BNAB活性的多特异性与 由于婴儿T/F病毒的这些功能反应降低了MTCT和自体病毒的风险 是传播的危险因素。此外，识别适合传输的BNAB逃生变体是 对于设计可以有效防止病毒传播的组合BNAB方法很重要。我们将 使用以下三个特定目标来检验我们的假设：（1）比较特异性和多功能性 来自传播和非传播母亲的血浆BNAB活性评估母体BNAB的作用 垂直病毒传播风险的活动。 （2）确定婴儿T/F病毒和循环病毒是否 与未转移的母亲相比，传播母亲更能抵抗血浆中和活性 来自传播和非传播母亲的母亲变体。 （3）定义负责的遗传特征 为了逃脱使用A的孕产妇特异性B细胞库中的变种 从传播母亲分离的天然ENV三聚体特异性单元格的面板。定义特异性和 可以减少病毒逃生并阻碍病毒的孕妇中和抗体的功能 传播对于设计可消除HIV的新型被动和主动疫苗方法至关重要 从母亲到婴儿的传播，是定义BNAB-未来使用的人口影响的工具 基于HIV传播动力学的预防。