AIDS Vaccine Strategy Using IgG Transfer Pathway

描述（由申请方提供）：人类免疫缺陷病毒（HIV）主要通过粘膜途径传播，强调HIV-1疫苗必须产生粘膜免疫应答。然而，粘膜免疫受到递送完整疫苗抗原穿过粘膜屏障以诱导有效粘膜免疫的能力的限制。该提案的长期目标是确定IgG跨细胞途径是否代表针对HIV和AIDS相关机会病原体感染的亚单位疫苗的新递送途径。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IgG跨极化上皮细胞的双向转运。最初认为FcRn通过胎盘将母体IgG转运至胎儿或通过肠道转运至新生儿。然而，FcRn在成人和动物的多种组织和细胞中表达; IgG是下呼吸道和生殖道中免疫球蛋白的主要同种型。基于这些证据，我们将检验以下假设：使用IgG转运途径，FcRn可将融合至IgG-Fc的HIV-1抗原穿过粘膜屏障递送至下层粘膜相关淋巴组织。这种运输的后果可能会引起能够在病毒进入港中和病毒的局部免疫和能够防止感染全身传播的全身免疫。HIV包膜糖蛋白gp 120将用于探测对这种免疫的免疫应答并定义保护性免疫应答。本提案的具体目的是确定FcRn递送gp 120-Fc抗原穿过生殖器或呼吸道粘膜屏障以产生针对粘膜病毒接种病毒攻毒的保护性免疫的能力。本文产生的数据将不仅为HIV疫苗的设计提供有价值的信息，而且为靶向AIDS相关的机会性病原体或其它病原体（例如巨细胞病毒、单纯疱疹病毒、分枝杆菌、衣原体、流感等）的一般疫苗策略提供有价值的信息，感染或侵入粘膜表面。

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.