AIDS Vaccine Strategy Using IgG Transfer Pathway

使用 IgG 转移途径的艾滋病疫苗策略

• 批准号: 7458667
• 负责人: XIAOPING ZHU
• 金额: $ 18.39万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7458667
• 关键词: AIDS Vaccines; Adult; Animals; Antibodies; Antigens; Apical; Cells; Chimeric Proteins; Chlamydia; Class; Clinic; Cytomegalovirus; Data; Epithelial; Epithelial Cells; Fc Immunoglobulins; Female; Fetus; Foundations; Genital system; Genus Mycobacterium; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV vaccine; HIV-1; Human; Immune response; Immunity; Immunization; Immunoglobulin G; Immunoglobulin Isotypes; Immunoglobulins; In Vitro; Infection; Influenza; Intestines; Invaded; Knockout Mice; Life; Lower respiratory tract structure; Lymphoid Tissue; Mediating; Mucosal Immune Responses; Mucosal Immunity; Mus; Neonatal; Newborn Infant; Pathway interactions; Patients; Placenta; Proteins; Rodent; Route; Simplexvirus; Subunit Vaccines; Surface; Testing; Thinking; Tissues; Vaccine Antigen; Vaccines; Vaccinia virus; Viral Antigens; Virus; Virus Diseases; base; concept; design; genital secretion; monolayer; mucosa-associated lymphoid tissue; neonatal Fc receptor; novel; pathogen; prevent; respiratory; transmission process; virus envelope

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.

描述（由申请人提供）：人类免疫缺陷病毒（HIV）的传播主要是通过粘膜途径发生的，强调HIV-1疫苗必须引起粘膜免疫反应。然而，粘膜免疫受到在粘膜屏障中输送完整的疫苗抗原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了针对HIV和与AIDS相关的机会性病原体的亚基疫苗的新型输送路径。该项目的目的来自最近的概念证明，即新生儿FC受体（FCRN）介导了IgG跨极化上皮细胞的双向转运。最初认为FCRN通过胎盘或通过肠道将母体IgG传递到胎儿或新生儿。但是，FCRN在成年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，我们将测试以下假设：使用IgG转运途径，FCRN可以将HIV-1抗原融合到IgG-FC上，跨粘膜屏障与下面粘膜相关的淋巴样组织。这种运输的后果可能会引起局部免疫力，能够在其进入港口中和病毒，并能够防止感染系统性扩散。 HIV包膜糖蛋白GP120将用于探测这种免疫的免疫反应并定义保护性免疫反应。该提案的具体目的是确定FCRN在生殖器或呼吸道粘膜上提供GP120-FC抗原的能力，从而产生抗MucosALLV接种病毒挑战的保护性免疫。本文生成的数据将不仅为艾滋病毒疫苗的设计提供有价值的信息，而且还将为靶向艾滋病相关的机会病原体或其他病原体（例如巨细胞病毒，单纯疱疹病毒，疱疹病毒，分枝杆菌，菌群，白斑，造影症等，跨越或遍布mucce cance cosal mucce sarface serface cossosal surface）。