MUCOSAL IMMUNIZATION STRATEGIES FOR PREVENTION OF AIDS

预防艾滋病的一些疫苗战略是 建议，包括使用减毒细菌和病毒载体 表达HIV、混合型肝炎颗粒的各种表位 表达VC环肽、表达gp120的DNA疫苗，以及 含HIV AS B细胞和T细胞表位的合成肽 免疫原。HIV亚基(gp120、gp160)和全杀性HIV已被 在人类和非人类灵长类动物身上进行了测试。所有这些都不是 有效。限制发展有效的艾滋病毒的一个主要问题 疫苗是预防艾滋病毒的免疫相关因素并不是 为人所知。在这份提案中，申请者提出了一项新的战略，以 通过接种疫苗预防艾滋病。他们已经开发出一种新的粘膜 一种佐剂，已在许多动物研究中证明能诱导 与全灭活细菌共用时的保护性免疫 或病毒，或这些病毒的亚基或相关的毒力决定因素 病原体。这种佐剂促进了两种抗原的发展- 特异性体液(抗体)和细胞免疫反应 在系统和粘膜间隔中的病原体。在……里面 此外，该佐剂最近进行了两个I期临床试验 在人体上的研究，已被证明是安全无毒的 佐剂-有效剂量。拟议的研究将集中在使用 该佐剂用于产生体液免疫和细胞免疫 对HIV抗原gp120模型的反应。这样做的主要目标是 这项研究是针对HIV的体液和细胞反应的特征 Gp120与佐剂一起使用时，并确定是否 对该抗原的体液或细胞免疫反应的性质 在该佐剂存在或不存在的情况下给药将受到影响 通过免疫的途径，或注射的剂量。 由于免疫保护与艾滋病毒感染的相关性尚不清楚， 接种疫苗引起的免疫反应类型将是 以深度为特征的。血清和粘膜抗gp120抗体将 根据抗原特异性免疫球蛋白进行测定和表征 酶联免疫吸附试验检测血清和粘膜分泌物中的同种异型及其分布 Western印迹和体外中和HIV感染性的能力。 将应用细胞研究来确定T辅助细胞的类型 效应期诱导的反应和细胞因子的变化 免疫反应，特别是TH1和TH1的发展 Th1类型反应，以及CTL活性。

A number of vaccine strategies for prevention of AIDS have been proposed, including use of attenuated bacterial and viral vectors expressing various epitopes from HIV, hybrid hepatitis particles expressing a VC loop peptide, DNA vaccines expressing gp120, and synthetic peptides containing B- and T-cell epitopes of HIV as immunogens. HIV subunits (gp120, gp160) and whole killed HIV have been tested in humans and non-human primates. None of these has been effective. A major problem limiting the development of an effective HIV vaccine is that the immune correlates of protection against HIV are not known. In this proposal, the applicants address a new strategy for prevention of AIDS by vaccination. They have developed a novel mucosal adjuvant which has been shown in numerous animal studies to induce protective immunity when coadministered with whole inactivated bacteria or viruses, or subunits or relevant virulence determinants from these pathogens. This adjuvant promotes the development of both antigen- specific humoral(antibody) and cell-mediated immune responses against the pathogen in both the systematic and mucosal compartments. In addition, the adjuvant has recently undergone two Phase I clinical studies in humans and has been shown to be safe and nontoxic at adjuvant-effective doses. The proposed studies will focus on the use of this adjuvant for production of humoral and cell-mediated immune responses against a model of HIV antigen - gp120. The main goal of this study is to characterize the humoral and cellular response against HIV gp120 when administered with the adjuvant, and to determine whether the nature of the humoral or cellular immune responses to this antigen when delivered in the presence or absence of this adjuvant will be influence by the route of immunization, or the number of doses administered. Since the immune protective correlates to HIV infection are unknown, the type of immune response induced by vaccination will be characterized in depth. Serum and mucosal anti-gp120 antibodies will be determined and characterized with respect to antigen-specific Ig isotypes and distribution in serum and mucosal secretions by ELISA and Western blot, and the ability to neutralize HIV infectivity in vitro. Cellular studies will be applied to determine the type of T helper cell response induced and the cytokine profile during the effector phases of the immune response, with special regard to development of TH1 and TH1 type response, as well as CTL activity.