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(申请人提供)：内皮细胞和上皮细胞是体内HCMV的主要靶点，也可能是先天性感染中病毒通过胎盘转移到胎儿的重要部位。在HCMV中，UL128-131位点的Gh/Gl糖蛋白复合体和病毒蛋白是内吞病毒进入内皮/上皮细胞所必需的。这种病毒进入途径与在成纤维细胞中发现的GB进入途径是分开的。针对UL128-UL131位点蛋白和内吞复合体的抗体可以中和病毒对内皮/上皮细胞的感染。我们假设，一种包括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一种更有效的预防先天性感染的疫苗。由于巨细胞病毒的种属特异性，本研究将利用豚鼠巨细胞病毒(GPCMV)进行。豚鼠是唯一可以研究先天性巨细胞病毒感染的小型动物模型。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之处是，当病毒在成纤维细胞系上生长时，UL128-131位点的缺失倾向。这种情况在HCMV和GPCMV中都会发生，这使得对内/上皮细胞的感染研究变得更加复杂。我们建议使用慢病毒转导的表达缺失GPCMV基因的tet-off互补细胞系(GP128-131)的新方法来产生假型GPCMV，编码推测的内吞途径的部分或全部组件。我们的假设是，我们将能够通过这一策略确定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，一旦鉴定出内吞途径蛋白复合体的最低组分，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，与缺乏该基因的DISC病毒相比，该策略将增强对先天性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，在免疫受损人群中会导致大量死亡和发病，包括移植和艾滋病患者以及宫内胎儿。先天性巨细胞病毒感染会导致存活新生儿的智力低下和耳聋。巨细胞病毒是艾滋病最常见的继发性感染。目前还没有针对CMV的疫苗。尽管目前的抗病毒药物可用于移植和艾滋病患者，但这些药物会导致出现导致疾病的耐药菌株。此外，抗病毒药物的毒副作用使其不能用于预防先天性巨细胞病毒。