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

抗体依赖性细胞毒性和 HIV-1 母婴传播

• 批准号: 10630722
• 负责人: Manish Sagar
• 金额: $ 69.98万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630722
• 关键词: Animal Model; Antibodies; Antibody Specificity; Autologous; Birth; Blood; Breast Feeding; Cells; Characteristics; Chronic; Clinical Trials; Data; Epitopes; Exposure to; Future; Generations; Genetic Transcription; HIV; HIV-1; Human; Human Milk; Immunoglobulin Somatic Hypermutation; Immunologic Factors; Immunotherapy; Individual; Infant; Infant Mortality; Infection; Inflammation; Infusion procedures; Integration Host Factors; Investigation; Lead; Maternal antibody; Mediating; Methodology; Monoclonal Antibodies; Morbidity - disease rate; Mothers; Plasma; Population; Predisposition; Pregnancy; Prevention trial; Property; RNA; Residual state; Resistance; Role; Sampling; Susceptibility Gene; T-Lymphocyte; Techniques; Testing; Vaccines; Variant; Vertical Disease Transmission; Viral; Viremia; Virus; Work; antibody-dependent cell cytotoxicity; antiretroviral therapy; base; cohort; exposed human population; improved; infant infection; inflammatory marker; insight; mortality; neutralizing antibody; novel; passive antibodies; pressure; prevent; resistant strain; response; transmission process; vaccine strategy; virus characteristic

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.

项目概要 超过 150,000 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药物 在某些人群中仍然无法获得治疗（cART）。令人惊讶的是，即使没有 cART，仅 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，例如母体抗体，可能会预防 传播。母婴传播 (MTCT) 队列是检查预传播影响的理想方法。 现有抗体可预防 HIV-1 在自然环境中传播，因为：1) 婴儿可靠 接触病毒； 2）母亲将抗体传递给婴儿； 3）样品可以从两者获得 传播之前和之后的母亲和婴儿。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，母婴传播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) 不能提供针对 HIV-1 传播的显着保护。 动物模型和 HIV-1 传播之间的主要区别在于人类暴露于不同的环境 HIV-1 变异群，其中一些菌株具有中和抗性。在暴露的地方 个体已经拥有 nAb，他们会获得中和抗性变体。相比之下，我们表明 预先存在针对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 年内发病率较低 缺乏 cART。我们进一步观察到传输取决于先前存在的 ADCC 广度 和在未接触过的婴儿中的效力以及在母体内循环的变异体的 ADCC 敏感性 变体（暴露菌株）。我们建议在期间为 ADCC 的重要性提供更明确的支持 母婴传播通过探索新感染的婴儿是否获得 ADCC 耐药菌株。我们将进一步确定宿主因素 影响 ADCC 广度和效力以及 ADCC 易感性的病毒特征。我们进一步 假设受感染婴儿中存在的 ADCC 可以消除带有传染性病毒的细胞，这些病毒可以产生 病毒。对于自体病毒具有较高 ADCC 的婴儿，残留感染细胞的数量较少。一个 受感染细胞数量较少，病毒血症和血浆炎症较低，从而降低发病率 和缺乏 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 广泛且有效的 ADCC 抗体。这些研究将提供有关这些特征的见解 抗体以及使用最先进的疫苗方法引发抗体的潜在新方法。这 拟议的研究将清楚地说明 ADCC 在传播过程中施加的选择压力，强调 预先存在的 ADCC 如何降低死亡率并导致新型保护性抗体的产生。 总而言之，这项工作将为开发有效的 HIV-1 疫苗提供新策略。