Antibody dependent cellular cytotoxicity and HIV-1 mother to child transmission

项目摘要 超过15万名婴儿从受感染的母亲那里感染艾滋病毒-1，主要是因为联合抗逆转录病毒药物。 在某些人群中仍然无法获得cART治疗。令人惊讶的是，即使在没有cART的情况下， 大约20 - 30%的婴儿从母亲那里感染HIV-1，尽管他们经常接触病毒 在妊娠、分娩和哺乳期间。免疫因素，如母体抗体，可能会阻止 传输母婴传播（MTCT）队列是检查预防艾滋病毒/艾滋病影响的理想方法。 现有的抗体在预防HIV-1在自然环境中的传播，因为：1）婴儿是可靠的 2）母亲将抗体传给婴儿; 3）样本可以从两个人身上获得。 母亲和婴儿在传播之前和之后。了解抗体的作用和类型 预防HIV-1传播仍然是最高优先事项之一，特别是对于疫苗工作而言。在 与所有动物模型相比，MTCT研究和抗体被动输注临床试验表明， 预先存在的中和抗体（nAb）不能提供显著的保护，防止HIV-1传播。 动物模型和HIV-1传播之间的主要区别是，人类暴露于多种多样的 一群HIV-1变种，其中一些菌株具有中和抗性。在暴露的环境中， 个体已经拥有nAb，他们获得中和抗性变体。相反，我们表明， 存在针对其母亲中和作用的抗体依赖性细胞毒性（ADCC）的婴儿 耐药菌株感染HIV-1的可能性较小，并且在出生后1年内， 没有CART。我们进一步观察到，传输取决于预先存在的ADCC宽度 初治暴露婴儿中的效力和母体中循环的变体的ADCC敏感性 变种（暴露菌株）。我们建议为ADCC的重要性提供更明确的支持， 通过探索新感染的婴儿是否获得ADCC耐药菌株进行MTCT。我们将进一步确定宿主因素 以及影响ADCC宽度和效力以及ADCC易感性的病毒特征。我们进一步 假设存在于感染婴儿中ADCC可以消除具有感染性病毒的细胞 病毒对自身病毒具有较高ADCC的婴儿具有较低数量的残留感染细胞。一 较少数量的感染细胞导致较低的病毒血症和血浆炎症，从而降低发病率 以及没有cART时的死亡率。最后，我们将使用最先进的技术来分离和表征 广泛和有效的ADCC抗体。这些研究将提供有关这些特征的见解， 抗体和使用现有技术疫苗方法学来引发它们的潜在新方法。的 拟议的研究将提供关于ADCC在传播过程中施加的选择压力的清晰度，强调 预先存在的ADCC如何降低死亡率，并导致新的保护性抗体的产生。 累积起来，这项工作将为开发有效的HIV-1疫苗提供新的策略。

PROJECT SUMMARY Over 150,000 infants acquire HIV-1 from their infected mothers primarily because combination antiretroviral treatment (cART) remains inaccessible in some populations. Surprisingly even in the absence cART, only around 20 – 30% of infants get HIV-1 from their mother although they are constantly exposed to the virus during gestation, birth and breast feeding. Immune factors, such as maternal antibodies, likely prevent transmission. Mother to child transmission (MTCT) cohorts are an ideal way to examine the impact of pre- existing antibodies in preventing HIV-1 transmission in a natural setting because: 1) infants are reliably exposed to the virus; 2) mothers pass their antibodies to the infant; and 3) samples can be obtained from both the mother and the infant prior to and after transmission. Understanding the role of and the types of antibodies that can prevent HIV-1 transmission remains one of the highest priorities especially for vaccine efforts. In contrast to all animal models, MTCT investigations and antibody passive infusion clinical trials demonstrate that pre-existing neutralizing antibodies (nAbs) do not provide significant protection against HIV-1 transmission. The major difference among animal models and HIV-1 transmission is that humans are exposed to a diverse swarm of HIV-1 variants, and some of the strains are neutralization resistant. In setting where the exposed individual already possesses nAbs, they acquire neutralization resistant variants. In contrast, we show that infants with pre-existing antibody dependent cellular cytotoxicity (ADCC) against their mother’s neutralization resistant strains are less likely to acquire HIV-1, and they have lower morbidity up to 1 year after birth in the absence of cART. We have further observed that transmission depends on both the preexisting ADCC breadth and potency in the naïve exposed infant and the ADCC sensitivity of the variants circulating in the maternal variants (exposure strains). We propose to provide more definitive support for the importance of ADCC during MTCT by exploring if newly infected infants acquire ADCC resistant strains. We will further identify host factors and virus characteristics that influence ADCC breadth and potency and ADCC susceptibility. We further hypothesize that ADCC present in infected infants can eliminate cells with infectious virus that can produce virus. Infants with higher ADCC against their autologous virus have a lower number of residual infected cells. A smaller number of infected cells results in lower viremia and plasma inflammation, which decreases morbidity and mortality in the absence of cART. Finally, we will use state of the art techniques to isolate and characterize broad and potent ADCC antibodies. These studies will provide insights about the characteristics of these antibodies and the potential novel ways to elicit them using state of the art vaccine methodologies. The proposed studies will provide clarity about the selection pressure ADCC exerts during transmission, highlight how pre-existing ADCC decreases mortality, and lead to the generation of novel protective antibodies. Cumulatively, this work will provide new strategies for developing an effective HIV-1 vaccine.