DEVELOPMENT OF AN AIDS PROTOTYPE VACCINE USING SIV

总体描述(改编自应用程序)：具有衰减的研究 巨噬细胞嗜性SIV/17E导致申请者假设 最好的艾滋病毒疫苗是减毒活疫苗、嗜巨噬细胞疫苗和粘膜疫苗。 送来了。他们建议证明这一假设，并探索 机制(S)，可加强和扩大保护，并 在人体试验中确定保护与援助的相关性。以特定的目标 1，研究人员计划确定免疫反应的差异 与全身免疫与直肠免疫相关的T嗜性(SIV239 DELTA NEF)与M嗜性(SIV/17E)疫苗。他们还将比较 暂时出现中和抗体、抗体亲和力、细胞 外周免疫反应和CD8+T细胞抑制活性 外周血中免疫球蛋白A、CD8+抑制物活性和CTL的变化 静脉和肠内感染猴肠道固有层的实验研究 用这两种疫苗进行直肠注射。在这些研究中，猴子将被 直肠，然后静脉注射SIV/DeltaB670。具体而言 目标2，申请者将识别SIV在年聘用的机制(S 逃避保护豁免权。重组感染性克隆携带 逃逸突变体的变异env序列的片段将是 由克莱门茨博士建造(项目4)。这些将被用来感染 猴子确定这些序列在T细胞和B细胞中的作用 免疫力、病毒嗜性和毒力。猴子们将面临挑战， 亲本变异体，用于识别参与的特定表位(S) 免疫逃逸。在特定目标3中，猴子将感染SIV/17E 和SIV/239表达TH1和TH2细胞因子(GM-CSF、IL-12、IL-5和 B7共刺激分子)来确定是否有定点表达 细胞因子可增强黏膜保护性免疫或 系统地。在特定目标4中，针对特定病毒的减毒疫苗 不同的HIV分支，将由Luciw博士(核心C)使用 需求显示最适合SIV，将进行评估以扩展 对HIV的认识和防护广度的确定 可能会有反应。

OVERALL DESCRIPTION (adapted from application): Studies with attenuated macrophage tropic SIV/17E have led the applicants to hypothesize that the best HIV vaccine is live attenuated, macrophage-tropic, and mucosally delivered. They propose to prove this hypothesis and to explore mechanism(s) whereby protection can be enhanced and broadened, and to identify correlates of protection to aid in human trials. In Specific Aim 1, the investigators plan to identify differences in immune responses associated with systemic versus rectal immunization with T-tropic (SIV239 delta nef) versus M-tropic (SIV/17E) vaccines. They will also compare the temporal emergence of neutralizing antibody, antibody avidity, cellular immune responses, and CD8+ T cell suppressor activity in the peripheral blood, and secretory IgA, CD8+ suppressor activity and CTL in the intestinal lamina propria in monkeys infected intravenously or intra- rectally with the two vaccines. In these studies, monkeys will be challenged rectally, then intravenously, with SIV/DeltaB670. In Specific Aim 2, the applicants will identify mechanism(s) employed by SIV in evading protective immunity. Recombinant infectious clones carrying fragments of variant env sequences from the escape mutant will be constructed by Dr. Clements (Project 4). These will be used to infect monkeys to determine the role of these sequences in T- and B-cell immunity, viral tropism, and virulence. Monkeys will be challenged with the parental variant to identify the specific epitope(s) involved in immune escape. In Specific Aim 3, monkeys will be infected with SIV/17E and SIV/239 expression TH1 and TH2 cytokines (gm-CSF, IL-12, IL-5, and the B7 co-stimulatory molecule) to determine whether site-directed expression of cytokines can augment protective immunity either mucosally or systematically. In Specific Aim 4, attenuated SHIV vaccines specific for different HIV clades, will be constructed by Dr. Luciw (Core C) using requirement show optimal for SIV, will be evaluated to both expand the understanding of HIV and to determine the breadth of the protective responses possible.