Mucosal SIV-CCR5 receptor vaccine in SIV infection

描述(由申请人提供)：该项目是开发一种针对艾滋病毒感染的疫苗策略，该策略基于一项“自然实验”，在A32 CCR5纯合子突变的受试者中发现对艾滋病毒感染的抵抗力。其具体目的是通过(A)阻断和下调参与原发粘膜HIV感染的CCR5辅助受体，以及(B)诱导粘膜、区域淋巴结和系统对病毒的免疫来建立Delta32CCR5突变的猿猴模型。该策略是使用微生物70kD热休克蛋白(HSP70)，它刺激CC趋化因子的产生，并起到佐剂的作用。用与HSP70连接的CCR5胞外肽免疫可产生抗CCR5抗体和CC趋化因子。这将通过使用SIV包膜gp120和Gag p27与特定的SIV靶向免疫相结合。SIV-CCR5疫苗将通过直肠途径在恒河猴体内进行免疫，并与接种SIV-HSP70或CCR5-HSP70的疫苗进行比较。在每次免疫之前和之后，将在粘膜和全身隔间监测基础广泛的先天和获得性免疫反应。这些动物将在第三次免疫后4周接受SIVmac 251的挑战。他们将被监测24周的血浆病毒载量、CD4v T细胞计数和干扰素，在此期间动物将被处死，并检测粘膜组织、淋巴结和脾中的病毒载量。这一新的免疫策略旨在产生先天性和获得性免疫，并针对病毒及其主要辅助受体，可能被证明是预防或控制艾滋病毒感染的有效方法。

DESCRIPTION (provided by applicant): The project is to develop a vaccine strategy against HIV infection that is based on an "experiment of nature" in which resistance to HIV infection is found in subjects with homozygous A32 CCR5 mutation. The specific aims are to develop a simian model of the delta32 CCR5 mutation by (a) blocking and downmodulating the CCR5 coreceptors which are involved in primary mucosal HIV infection and (b) eliciting mucosal, regional lymph node and systemic immunity against the virus. The strategy is to use a microbial70kD heat shock protein (HSP70) which stimulates production of CC chemokines and functions as an adjuvant. Immunization with the extracellular peptides of CCR5 linked toHSP70 elicits antibodies to the CCR5, as well as CC chemokines. This will be combined with specific SIV targeted immunization, by using SIV envelope gp120 and gag p27. Immunization with the SIV-CCR5 vaccine will be carried out by the rectal route in rhesus macaques and compared with those administered SIV-HSP70 or CCR5-HSP70. Broadly based innate and adaptive immune responses will be monitored in themucosal and systemic compartments before and after each immunization. The animals will be challenged 4 weeks after the 3 rd immunization with SIVmac 251. They will be monitored for plasma viral load, CD4 v T cell count and IFN'y for 24 weeks, at which time the animals will be killed and the viral load determined in mucosal tissues, lymph nodes and spleen. This novel immunization strategy, designed to generate innate and adaptive immunity, and targeting both the virus and its primary coreceptors may prove an effective approach in preventing or controlling HIV infection.