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

摘要 每年超过15万名艾滋病毒-1婴儿通过母婴传播(MTCT)感染，占 占全球每年HIV-1感染者的近10%。甚至实施高效的抗逆转录病毒治疗 (抗逆转录病毒治疗)不能阻止多达5%的HIV-1感染妇女将病毒传播给她们的婴儿。因此， 消除母婴传播需要与抗逆转录病毒药物疗法协同的方法。最有希望的干预措施 正在开发的预防艾滋病毒感染的临床方法包括被动给药或主动诱导 广谱中和抗体(BNAbs)。然而，矛盾的是，母体血浆中广泛的中和活性 一直与婴儿传播的风险有关，这引发了人们对这些方法的安全性的担忧 怀孕了。因此，需要更好地了解母体中和活动和母婴传播风险的作用。 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母婴传播。 HIV MTCT是一种独特的传播途径，它发生在预先存在的针对 自体病毒。我们之前发现婴儿中的传播/创始人(T/F)病毒具有更强的抵抗力 与非传播的母体病毒相比，配对的母体血浆中和作用更强。此外，我们还建立了 母体血浆中的bNab活性可以推动循环病毒逃逸变异体的发展 成为婴儿T/F病毒。我们假设母体血浆bNab活性的多特异性与 降低了MTCT和自体病毒逃避婴儿T/F病毒的这些功能反应的风险 是传播的风险因素。此外，识别适合于传播的bNab转义变体是 对于设计能够有效防止病毒传播的bNab组合方法非常重要。我们会 使用以下三个具体目标来检验我们的假设：(1)比较专一性和多功能性 从传播和非传播母亲的血浆bNab活性来评估母亲bNab的作用 活动中存在垂直传播病毒的风险。(2)确定婴儿流行性感冒病毒和流行性出血热病毒 传播的母亲比未传播的母亲对血浆中和活性的抵抗力更强 传播型和非传播型母亲的母体变异。(3)定义负责的遗传签名 在通过母体传播的婴儿环境病毒变异体中，使用 从传播性母亲中分离出来的本地环境三聚体特异性单抗小组。定义了其特殊性和 预先存在的母体中和抗体的功能可以减少病毒逃逸和阻碍 传播将是设计能够消除艾滋病毒的新型被动和主动疫苗方法的关键 从母亲到婴儿的传播，是定义未来使用bNab对人口影响的工具- 基于艾滋病毒传播动态的预防措施。

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.