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

项目总结 超过15万名婴儿从受感染的母亲那里感染HIV-1，主要是因为联合抗逆转录病毒 在一些人群中，仍然无法获得治疗(购物车)。令人惊讶的是，即使在没有手推车的情况下，只有 大约20%-30%的婴儿从母亲那里感染了HIV-1，尽管他们经常接触这种病毒 在怀孕、分娩和哺乳期间。免疫因素，如母体抗体，可能会阻止 变速箱。母婴传播(MTCT)队列是检查母婴传播前疾病影响的理想方法 在自然环境中预防HIV-1传播的现有抗体，因为：1)婴儿可靠 暴露在病毒中；2)母亲将她们的抗体传递给婴儿；3)样本可以从两者中获得 母亲和婴儿在传播之前和之后。了解抗体的作用和类型 预防艾滋病毒-1传播仍然是最高优先事项之一，特别是在疫苗工作中。在……里面 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 先前存在的中和抗体(NAB)不能对艾滋病毒-1传播提供重大保护。 动物模型和HIV-1传播之间的主要区别是，人类接触到不同的 大量的HIV-1变异株，其中一些毒株具有中和抗性。在设置暴露的地方 个体已经拥有nabs，他们获得了中和抗性变种。相反，我们展示了 已存在抗体依赖细胞毒性(ADCC)的婴儿对其母亲的中和反应 耐药菌株感染HIV-1的可能性较小，而且在出生后一年内发病率较低 没有手推车。我们进一步观察到，传输取决于先前存在的ADCC宽度 在幼稚暴露的婴儿中的效力和在母亲体内循环的变异体的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耐药株进行MTCT。我们将进一步确定主机因素 以及影响ADCC广度和效力以及ADCC易感性的病毒特征。我们进一步 假设感染婴儿体内的ADCC可以清除感染病毒的细胞，这些细胞可以产生 病毒。对自体病毒有较高ADCC的婴儿残留感染细胞数量较少。一个 感染细胞数量较少会降低病毒血症和血浆炎症，从而降低发病率。 以及在没有购物车的情况下死亡。最后，我们将使用最先进的技术来分离和表征 广泛而有效的ADCC抗体。这些研究将提供关于这些特征的见解 抗体和潜在的新方法，以引出它们使用最先进的疫苗方法。这个 拟议的研究将澄清ADCC在传输过程中施加的选择压力，重点是 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。 总而言之，这项工作将为开发有效的艾滋病毒-1疫苗提供新的战略。

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.