Fc-Mediated Antibody Responses in HIV-1 Mother-to-Child Transmission

描述(申请人提供)：HIV疫苗的一个目标是诱导抗体，通过中和病毒或杀死受感染的细胞来预防感染。目前，来自人类疫苗试验的DAT对免疫相关的保护作用有限。然而，母婴传播(MTCT)提供了另一个独特的环境，在其中研究预先存在的抗体在保护中的作用。婴儿在子宫内接受被动转移的艾滋病毒特异性抗体，这可能会保护婴儿免受母乳喂养期间的感染。这项建议利用了 1992年至1998年，来自肯尼亚内罗毕的艾滋病毒阳性母亲及其婴儿进行了一次独特的队列调查。被研究的婴儿在出生时都没有感染，但通过母乳喂养持续接触病毒，因此有感染的风险。利用这个队列，我们将重点研究Fc介导的抗体反应在MTCT中的作用。其中一种反应是抗体依赖的细胞毒性(ADCC)，它已被证明影响恒河猴和人类的HIV-1感染和疾病进展。这项研究将解决这一假设，即被动获得的抗体介导的ADCC活动与艾滋病毒阳性母亲所生婴儿的感染风险呈负相关。由于ADCC的活性是通过抗体的Fc部分介导的，并且Fc受体(FCR)基因与不同的抗体结合相关，我们还将研究FCR基因在HIV感染和进展中的作用。最后，本提案的第三部分将审查自体ADCC反应在母婴传播中的作用。在这些实验中，ADCC检测将被定制，以测试每个婴儿针对他们接触到的母体病毒抗原的抗体，同时利用携带婴儿FCR型(S)的效应细胞。总体而言，这些研究将提供有关先前存在的ADCC抗体和宿主遗传学在母婴传播中的作用的知识。这些数据将有助于为未来的疫苗研究提供信息，并为可能影响疫苗有效性的宿主因素提供洞察。

DESCRIPTION (provided by applicant): One goal of an HIV vaccine is to elicit antibodies that protect against infection by either neutralizing virus or killing infected cells. At this time, dat from human vaccine trials on the immune correlates of protection are limited. Mother-to-child transmission (MTCT), however, provides another unique setting in which to study the role of pre-existing antibodies in protection. Infants receive passively transferred HIV-specific antibodies in utero that may protect against infection during breastfeeding. This proposal utilizes a unique cohort of HIV-positive mothers and their infants from Nairobi, Kenya conducted from 1992 to 1998. The infants to be studied were all uninfected at birth but continually exposed to the virus via breastfeeding, and thus at risk for infection. Using this cohort, we will focus on th role of Fc-mediated antibody responses in MTCT. One such response is antibody-dependent cellular cytotoxicity (ADCC), which has been shown to influence HIV-1 acquisition and disease progression in macaques and humans. This study will address the hypothesis that ADCC activity mediated by passively acquired antibodies is inversely correlated with risk of infection i infants born to HIV-positive mothers. As ADCC activity is mediated through the Fc portion of the antibody and Fc receptor (FcR) genotype correlates with differential antibody binding, we will also examine the role of FcR genotype on HIV acquisition and progression. Finally, the third part of this proposal will examine the role of autologous ADCC responses in MTCT. In these experiments, ADCC assays will be customized to test each infant's antibodies against maternal viral antigens to which they were exposed, while utilizing effector cells bearing the FcR genotype(s) of the infant. Overall, these studies will provide knowledge on the role of pre-existing ADCC antibodies and host genetics in MTCT. These data will help inform future vaccine studies and provide insight into host factors that may influence vaccine effectiveness.