Neutralizing and non-neutralizing antibodies protection from breast milk HIV-1

描述（由申请人提供）：确定免疫因子，防止艾滋病毒-1收购仍然是该领域的首要任务。检查反复暴露于HIV-1但未被感染的受试者（HESN）可用于确定保护的相关性。与注射吸毒或性接触HESN队列相反，反复暴露于母亲母乳中的病毒的婴儿是理想的受试者，因为人们可以获得来自暴露个体和暴露病毒的样本。我们假设，暴露的婴儿中存在的抗体会影响母体HIV-1变异体建立感染的可能性。以前的非人类灵长类动物研究强烈表明，抗体可以帮助阻断病毒传播，但没有直接的人类证据表明预先存在的抗体可以阻断HIV-1的获得。与使用超生理水平抗体阻断无细胞攻击病毒的被动免疫研究相反，婴儿感染可能发生于母乳中的细胞相关或无细胞变体，这些变体可能不 对婴儿体内已有的抗体很敏感我们建议测试的假设，婴儿抗体，可以特异性地阻止母体的变异，防止HIV-1的收购。除了发现母乳喂养期间抗体的存在和传播之间的相关性外，我们还将研究保护机制。抗体可以起到保护作用，因为它们可以通过阻止病毒最初进入易感宿主细胞来中和病毒。另一方面，免疫效应细胞，如自然杀伤细胞，可以通过抗体依赖性细胞毒性消除母体母乳无细胞病毒和感染细胞。最后，抗体可以防止病毒附着到肠道归巢受体，？四个？7，这可以防止病毒感染注定迁移到肠道相关淋巴组织（GALT）的易感细胞。因为在初始入侵后，GALT内发生高水平复制，阻断病毒到达这些重要的隔室可能会防止母体变异在暴露的婴儿中建立全身感染。我们提出的研究将提供第一个直接证据，表明预先存在的抗体对暴露有活性， 病毒可以阻止HIV-1感染。此外，我们的机制研究将可能为我们提供信息， 疫苗免疫原应引起的抗体特性和特异性。我们的研究将对未来的HIV-1疫苗工作产生重要影响。 公共卫生相关性：由于暴露病毒和婴儿血浆的可用性，通过检查母婴二对体之间的母乳传播，可以理想地确定保护免受HIV-1感染的因素。我们假设，抗体，无论是中和传入的病毒，诱导自然杀伤细胞效应器功能或阻断migratin肠道相关淋巴组织是重要的，在防止HIV-1收购。证明抗体可以减少HIV-1的传播，并了解这种保护的具体机制，对未来的疫苗工作非常重要。

DESCRIPTION (provided by applicant): Identifying the immune factors that protect against HIV-1 acquisition remains a top priority within the field. Examining subjects who are repeatedly exposed to HIV-1 but do not become infected (HESN) can be used to identify the correlates of protection. As opposed to injection drug use or sexual contact HESN cohorts, infants repeatedly exposed to virus from their mother's breast milk are ideal subjects because one has access to both samples from the exposed individual and the exposure virus. We hypothesize that antibodies present in an exposed infant influence the likelihood of maternal HIV-1 variants in establishing infection. Previous non- human primate studies strongly suggest that antibodies can help block virus transmission, but there is no direct human evidence that preexisting antibodies can block HIV-1 acquisition. In contrast to the passive immunization studies which use supra-physiologic levels of antibodies that can block cell-free challenge virus, infant infections may occur from cell-associated or cell-free variants in the breast milk that are may not be susceptible to the infant's pre-existing antibodies. We propose to test the hypothesis that infant antibodies that can specifically block the maternal variants protect against HIV-1 acquisition. In addition to finding correlations between the presence of antibodies and transmission during breast feeding, we will examine the mechanisms of protection. Antibodies may protect because they can neutralize a virus by preventing initial entry into a susceptible host cell. On the other hand, immune effector cells, such as natural killer cells, may eliminate maternal breast milk cell free viruses and infected cells through antibody dependent cellular cytotoxicity. Finally antibodies may prevent virus attachment to the gut homing receptor, ?4?7, which may prevent the virus from infecting susceptible cells destined to migrate to gut associated lymphoid tissue (GALT). Because after initial invasion, high level replication occurs within GALT, blocking the virus from reaching these important compartments may prevent the maternal variants from establishing a systemic infection within an exposed infant. Our proposed studies will provide the first direct evidence that pre-existing antibodies active against exposure viruses can prevent HIV-1 acquisition. In addition, our mechanistic studies will potentially inform the antibodies properties and specificities that should be elicited with vaccine immunogens. Our studies will have important implications for future HIV-1 vaccine efforts. PUBLIC HEALTH RELEVANCE: Identifying factors that protect against HIV-1 acquisition can be ideally identified by examining breast milk transmission among mother infant dyads because of availability of both the exposure virus and baby plasma. We hypothesize that antibodies that either neutralize the incoming virus, induce natural killer cell effector function or block migratin to the gut associated lymphoid tissue are important in protecting against HIV-1 acquisition. Showing that antibodies can decrease HIV-1 transmission and understanding the specific mechanisms for the protection will be important for future vaccine efforts.