ENHANCEMENT OF MUCOSAL IMMUNE RESPONSES TO HIV GP160

描述(改编自申请人的摘要)：诱导 对人类免疫缺陷病毒(HIV)的保护性免疫尚未 免疫效应器机制也没有被识别出来，可以预防或 至少控制最初的感染。鉴于这些困难，一个 开发艾滋病毒疫苗的有吸引力的战略是允许 多种HIV蛋白的表达及其诱导的多向免疫 回应。易于设计的脱氧核糖核酸(DNA)病毒载体，如 如痘病毒(布勒实验室)或疱疹病毒(莫里森实验室) 符合这些标准，将有助于为年轻人接种疫苗 成年人群，其中媒介特异性免疫力较低。痘病毒 表达多个HIV-1抗原的重组体已被证明是 在人体临床试验中是安全的，并诱导中和抗体和 针对多种HIV蛋白的细胞毒性T淋巴细胞(CTL)。这个 申请者正在构建复制缺陷疱疹病毒和痘病毒 编码HIV gp160的载体以及增强复制的因素 和运输树突状细胞(DC)和单核细胞以增强免疫 对gp160的反应诱导。提炼这些病毒的一个重要方面 载体将最大化对载体编码的HIV的免疫反应 蛋白质，包括提高艾滋病毒包膜的免疫原性 通过促进蛋白质的分泌和抗原的靶向摄取 递呈细胞(APC)。在这个项目中，疱疹病毒和痘病毒基因 编码干扰诱导免疫反应的蛋白质 被病毒感染的细胞将被灭活。其次，调查人员 建议对分泌单纯疱疹病毒的载体的形式进行改造 (HSV)VP22-gp160或CD3-gp60融合蛋白。申请者的假设 这些融合蛋白将通过靶向摄取来扩大APC池 邻近细胞(VP22融合)或特异性结合DC和B细胞(CD3 融合)被载体表达的免疫增强分子所吸引。最后， 申请者提出了一种利用粘膜的免疫方案 活病毒载体的管理，以及顺序免疫 疱疹和痘病毒载体可最大限度地减少 病媒特异性免疫。长期目标是创造病毒 增强和扩大免疫反应的HIV载体疫苗 在粘膜表面感染艾滋病毒。复制缺陷型单纯疱疹病毒的研究 HIV的疫苗载体也增加了耐人寻味的可能性 防止性传播疾病的组合疫苗。

DESCRIPTION (adapted from the applicant's abstract): Epitopes that induce protective immunity against human immunodeficiency virus (HIV) have not yet been identified, nor have the immune effector mechanisms that can prevent or at least control initial infection. In view of these difficulties, an attractive strategy for HIV vaccine development is one that permits expression of multiple HIV proteins and elicits a multifaceted immune response. Easily engineered, deoxyribonucleic acid (DNA) virus vectors such as poxviruses (Buller laboratory) or herpesviruses (Morrison laboratory) fulfill these criteria and would be useful for vaccination of the young adult population, in whom vector-specific immunity is low. Poxvirus recombinants expressing a number of HIV-1 antigens have been shown to be safe in human clinical trials and to induce neutralizing antibody and cytotoxic T lymphocytes (CTL) specific for multiple HIV proteins. The applicants are constructing replication-defective herpesvirus and poxvirus vectors that encode HIV gp160 as well as factors that enhance replication and trafficking of dendritic cells (DC) and monocytes to augment immune response induction to gp160. An important aspect in refining these virus vectors will be maximization of immune responses to the vector-encoded HIV proteins, including improvement of the immunogenicity of the HIV envelope proteins by facilitating their secretion and targeted uptake by antigen presenting cells (APC). In this project, herpesvirus and poxvirus genes encoding proteins that interfere with induction of immune responses to virus-infected cells will be inactivated. Secondly, the investigators propose to engineer forms of the vectors that secrete herpes simplex virus (HSV) VP22-gp160 or Cd3-gpl60 fusion proteins. The applicants hypothesize that these fusion proteins will expand the APC pool by targeting uptake to neighboring cells (VP22 fusion) or specifically to DC and B cells (Cd3 fusion) attracted by vector-expressed immune enhancing molecules. Finally, the applicants' propose an immunization protocol that utilizes mucosal administration of the live virus vector, and sequential immunization with herpes and poxvirus vectors to minimize the dampening effect of vector-specific immunity. The long-range goal is the creation of virus vector-based vaccines against HIV that intensify and expand immune responses to HIV at mucosal surfaces. Investigation of replication-defective HSV as a vaccine vector for HIV also raises the intriguing possibility of a combinatorial vaccine against sexually transmitted diseases.