Vaccine against CMV endothelial tropism & congenital infection

抗 CMV 内皮趋向性疫苗

• 批准号: 8240627
• 负责人: ALISTAIR MCGREGOR
• 金额: $ 18.38万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240627
• 关键词: Acquired Immunodeficiency Syndrome; Adverse effects; Animal Model; Antibodies; Antibody Formation; Antigen Targeting; Antigens; Antiviral Agents; Cavia; Cell Line; Cells; Complement; Complex; Complication; Coupled; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Disabled Persons; Disease; Endothelial Cells; Epithelial Cells; Evaluation; Fetus; Fibroblasts; Funding; Generations; Genes; Glycoproteins; Guinea pig cytomegalovirus; Homologous Gene; Human; Immune response; Immunocompromised Host; Inactivated Vaccines; Individual; Infection; Intervention; Length; Life; Mental Retardation; Morbidity - disease rate; Newborn Infant; Outcome Study; Pathway interactions; Patients; Phase III Clinical Trials; Placenta; Population; Pre-Clinical Model; Prevention; Production; Proteins; Recombinants; Research; Risk; Safety; Serum; Site; Species Specificity; Structure; Subfamily lentivirinae; Subunit Vaccines; System; Testing; Tetanus Helper Peptide; Transplantation; Tropism; United States National Institutes of Health; Vaccinated; Vaccine Design; Vaccines; Viral; Viral Antigens; Viral Proteins; Viral Vaccines; Virus; Virus Diseases; Work; base; congenital cytomegalovirus; congenital infection; deafness; design; immunogenic; improved; in utero; in vivo; interest; model development; mortality; neutralizing antibody; novel; novel strategies; novel vaccines; pathogen; protein complex; public health priorities; resistant strain; secondary infection; tissue culture; vaccine development; vaccine efficacy

DESCRIPTION (provided by applicant): Endothelial and epithelial cells are a major target in vivo for HCMV and potentially an important site for initiation of virus transfer across the placenta to the fetus in congenital infection. In HCMV, the gH/gL glycoprotein complex and viral proteins from the UL128-131 locus are required for endocytic viral entry into endothelial/epithelial cells. This viral entry pathway is separate from the gB entry pathway found in fibroblast cells. Antibodies against proteins of the UL128-UL131 locus and endocytic complex can neutralize virus infection of endothelial/epithelial cells. We hypothesize that a vaccine strategy which includes components of the endocytic viral entry pathway as neutralizing target antigens would be a more effective vaccine against congenital infection. The studies will be carried out using guinea pig cytomegalovirus (GPCMV) because of species specificity of HCMV. The guinea pig is the only small animal model that allows the study of congenital cytomegalovirus infection. An added complication of studying bona fide full length CMV and virus entry into endothelial/epithelial cells is the propensity for deletion of the UL128-131 locus when virus is grown on fibroblast cell lines. This happens in both HCMV and GPCMV, which complicates infection studies on endo/epithelial cells. We propose to use a novel approach of a lentivirus transduced tet-off complementing cell line system expressing missing GPCMV genes (GP128-131) to produce pseudotyped GPCMV encoding part or all of the components of the presumed endocytic pathway. Our hypothesis is that we will be able to determine the relevant proteins necessary for the endocytic pathway of GPCMV infection of endothelial cells via this strategy. Furthermore, we hypothesize that once the minimum components of the endocytic pathway protein complex are identified they can be included as part of a novel vaccine strategy based on a replication impaired (DISC) virus which will enhance the protective immune response against congenital CMV compared to a DISC virus lacking this locus. PUBLIC HEALTH RELEVANCE: Cytomegalovirus (CMV) is a ubiquitous pathogen that causes significant mortality and morbidity in immunocompromised populations including transplant and AIDS patients and the fetus in utero. Congenital CMV infection causes mental retardation and deafness in surviving newborn. CMV is the most common AIDS related secondary infection. There is no vaccine to CMV. Although current antivirals are available for transplant and AIDS patients these result in the emergence of resistant strains that cause disease. Additionally, antiviral drug toxic side effects preclude their use in the prevention of congenital CMV.

描述（由申请人提供）：内皮细胞和上皮细胞是 HCMV 体内的主要靶标，并且可能是先天性感染中病毒穿过胎盘转移至胎儿的重要起始位点。在 HCMV 中，gH/gL 糖蛋白复合物和来自 UL128-131 位点的病毒蛋白是内吞病毒进入内皮/上皮细胞所必需的。该病毒进入途径与成纤维细胞中发现的 gB 进入途径是分开的。针对 UL128-UL131 基因座和内吞复合物的蛋白质的抗体可以中和内皮/上皮细胞的病毒感染。我们假设，包含内吞病毒进入途径的成分作为中和靶抗原的疫苗策略将是针对先天性感染的更有效的疫苗。由于 HCMV 的物种特异性，这些研究将使用豚鼠巨细胞病毒 (GPCMV) 进行。豚鼠是唯一可以研究先天性巨细胞病毒感染的小动物模型。研究真正的全长 CMV 和病毒进入内皮/上皮细胞的另一个复杂因素是，当病毒在成纤维细胞系上生长时，UL128-131 位点的缺失倾向。这种情况发生在 HCMV 和 GPCMV 中，这使得内皮细胞/上皮细胞的感染研究变得复杂。我们建议使用表达缺失 GPCMV 基因 (GP128-131) 的慢病毒转导的 tet-off 互补细胞系系统的新方法来产生编码假定的内吞途径的部分或全部组件的假型 GPCMV。我们的假设是，通过这种策略，我们将能够确定 GPCMV 感染内皮细胞的内吞途径所需的相关蛋白质。此外，我们假设，一旦确定了内吞途径蛋白复合物的最小成分，它们就可以作为基于复制受损（DISC）病毒的新型疫苗策略的一部分，与缺乏该位点的 DISC 病毒相比，该策略将增强针对先天性 CMV 的保护性免疫反应。 公共卫生相关性：巨细胞病毒 (CMV) 是一种普遍存在的病原体，可导致免疫功能低下人群（包括移植患者、艾滋病患者以及子宫内胎儿）显着死亡和发病。先天性巨细胞病毒感染会导致幸存新生儿智力低下和耳聋。 CMV 是最常见的艾滋病相关继发感染。目前尚无针对 CMV 的疫苗。尽管目前的抗病毒药物可用于移植患者和艾滋病患者，但这些药物会导致导致疾病的耐药菌株的出现。此外，抗病毒药物的毒副作用使其无法用于预防先天性巨细胞病毒。