ROLE OF NEUTRALIZING ANTIBODIES IN TRANSMISSION OF SHIV

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 母体中和抗体(NABS)在确定婴儿是否 在艾滋病毒-1的母婴传播(MTCT)期间被感染的情况尚不清楚。 更高水平的自体和异源NAB与非 传播，以及耐NAB的菌株被传播。这一主题恰逢其时 重要的是，人们对测试疫苗或免疫疗法的兴趣越来越大 在母乳喂养早期，产后传播风险最高 药物治疗可以选择耐药菌株。是不是扩大了 人单克隆被动转移母源NAB在治疗中的作用 这个环境？为了在诊所外通过实验解决其中一些问题， 我们已经建立了新月形吸虫和木霉的围产期传播模型。在这个模型中，我们观察到在口服感染SHV-SF162P3的新生猕猴中，存在亚灭菌水平的免疫球蛋白G中和挑战病毒的持久血浆病毒控制。我们已经证明，被动转移的NaB可以加速从头开始的反Shiv NAB，类似于在SIV模型中的实验。在这次更新中，我们建议将重点转移到了解机制上 在这些观察的背后。获胜目标1，我们计划全面评估反- SHIV-Ig G免疫处理和对照成年猕猴的SHIV T和B细胞应答 大小、时间、亲和力、特异性、构象依赖性和广度。在AIM中 2，我们计划表征猕猴体内特异性B细胞反应的发展 通过克隆抗体变量加速与正常中和反应 单个抗体分泌B细胞(ASCs)的区域并将其重建为 人免疫球蛋白1抗体。通过这种方法，我们可以捕捉到早期免疫球蛋白的多样性 应答和鉴定环境特异性单抗的抗病毒活性，包括 中和和ADCVI。在目标3中，我们将测试新的艾滋病毒环境的有效性- 作为一种更有效的新生儿被动免疫疗法，特异性广中和单抗可补充母体SIV-Ig G。我们认为，这些实验将产生关于抗体在体内控制HIV的机制的有价值的信息，并可能为限制MTCT在临床上的应用提供潜在的免疫疗法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The role of maternal neutralizing antibodies (NAbs) in determining whether an infant becomes infected during Mother to Child Transmission (MTCT) of HIV-1 is unclear. Higher levels of both autologous and heterologous NAbs are associated with non- transmission, and NAb-resistant isolates are transmitted. This topic is timely and important, as there is increasing interest in testing vaccines or immunotherapies during the early breastfeeding period, when postpartum transmission risk is highest and drug therapy can select resistant isolates. Would the augmentation of the passively transferred maternal NAbs with human monoclonals (mAbs) be effective in this setting? To address some of these questions experimentally outside the clinic, we have established a perinatal SHIV transmission model in M. nemestrina and in M. mulatta. In this model, we have observed durable plasma virus control in newborn macaques infected orally with SHIV- SF162P3 in the presence of sub-sterilizing levels of IgG that neutralized the challenge virus. We have shown that passively transferred NAbs can accelerate de novo anti-SHIV NAbs, similar to experiments in the SIV model. In this renewal, we propose to shift the focus toward understanding the mechanisms behind these observations. WIn AIM 1, we plan to comprehensively evaluate the anti- SHIV T- and B-cell responses in SHIV-IgG-treated and control adult macaques for magnitude, timing, avidity, specificity, conformation-dependence, and breadth. In AIM 2, we plan to characterize the development of specific B cell responses in macaques with accelerated versus normal neutralizing responses by cloning antibody variable regions from individual antibody-secreting B cells (ASCs) and reconstructing them as human IgG1 antibodies. By this method, we can capture the diversity of the early IgG response and characterize the Env-specific mAbs for antiviral activity including neutralization and ADCVI. In AIM 3, we will test the effectiveness of new HIV Env- specific broadly neutralizing mAbs in complementing maternal SHIV-IgG as a more effective passive immunotherapy in newborns. We propose that these experiments will yield valuable information about the mechanisms of antibodies in controlling HIV in vivo and may inform potential immunotherapies to limit MTCT in the clinic.