AIDS Vaccine Strategy Using IgG Transfer Pathway

描述(由申请人提供)：人类免疫缺陷病毒(HIV)的传播主要通过粘膜途径，强调HIV-1疫苗必须产生粘膜免疫反应。然而，黏膜免疫一直受到通过黏膜屏障运送完整疫苗抗原以诱导有效粘膜免疫的能力的限制。这项建议的长期目标是确定免疫球蛋白跨细胞途径是否代表了针对艾滋病毒和艾滋病相关机会性病原体感染的亚单位疫苗的一种新的传递途径。该项目的目标源于最近的概念证明，即新生儿Fc受体(FcRN)介导了免疫球蛋白通过极化上皮细胞的双向运输。FcRN最初被认为是通过胎盘将母体免疫球蛋白运送到胎儿或通过肠道运送给新生儿。然而，FcRN在成年人类和动物的各种组织和细胞中都有表达；IgG是下呼吸道和生殖道中的一种主要的免疫球蛋白亚型。基于这些证据，我们将检验一种假设，即通过免疫球蛋白转运途径，FcRN可以将融合到免疫球蛋白-Fc的HIV-1抗原穿过粘膜屏障运送到底层的粘膜相关淋巴组织。这种运输的后果可以诱导能够在入境口岸中和病毒的本地免疫，以及能够防止感染的系统性传播的系统免疫。HIV包膜糖蛋白gp120将被用来探测对这种免疫的免疫反应，并定义保护性免疫反应。这项建议的具体目的是确定FcRN是否有能力通过生殖器或呼吸道粘膜屏障运送gp120-Fc抗原，以产生针对黏膜病毒攻击的保护性免疫。这些数据不仅将为HIV疫苗的设计提供有价值的信息，还将为针对艾滋病相关机会性病原体或其他病原体的一般疫苗策略提供有价值的信息，如巨细胞病毒、单纯疱疹病毒、分枝杆菌、衣原体、流感等，这些病原体感染或侵袭粘膜表面。

DESCRIPTION (provided by applicant): Transmission of Human Immunodeficiency Virus (HIV) occurs primarily via the mucosal routes, emphasizing HIV-1 vaccines must need to engender mucosal immune responses. However, mucosal immunization has been limited by the ability to deliver intact vaccine antigens across the mucosal barrier for induction of effective mucosal immunity. The long-term goal of this proposal is to determine whether the IgG transcellular pathway represents a novel delivery path for a subunit vaccine against infections of HIV and AIDS-related opportunistic pathogens. The goal of the project derives from the recent proof of concept that the neonatal Fc receptor (FcRn) mediates the bi-directional transport of IgG across polarized epithelial cells. FcRn was initially considered to transport maternal IgG to a fetus through the placenta or to newborns via the intestine. However, FcRn is expressed in a variety of tissues and cells in adult humans and animals; IgG is a predominant isotype of immunoglobulins in the lower respiratory and genital tract. Based on these evidences, we will test the hypothesis that using IgG transport pathway, FcRn can deliver HIV-1 antigen fused to an IgG-Fc across the mucosal barrier to the underlying mucosa-associated lymphoid tissue. The consequences of such transport could induce local immunity able to neutralize the virus at their port of entry and systemic immunity able to prevent systemic spread of the infection. HIV envelope glycoprotein gp120 will be used to probe immune responses to such immunization and to define protective immune responses. The specific aim of this proposal is to determine the ability of FcRn to deliver gp120-Fc antigen across the genital or the respiratory mucosal barrier to engender protective immunity against mucosallv-inoculated virus challenge. Data generated herein will provide valuable information not only for design of a HIV vaccine, but also for general vaccine strategy targeting AIDS-associated opportunistic pathogens or other pathogens, such as cytomegalovirus, herpes simplex virus, mycobacterium, chlamydia, influenza, etc., that infect at or invade across mucosal surfaces.