Mucosal SIV-CCR5 receptor vaccine in SIV infection

描述（由申请人提供）：该项目旨在开发一种针对艾滋病毒感染的疫苗策略，该策略基于“自然实验”，在该实验中，在具有A32 CCR5纯合突变的受试者中发现了对艾滋病毒感染的抵抗力。具体目标是通过(a)阻断和下调参与原发粘膜HIV感染的CCR5辅助受体，(b)激发粘膜、区域淋巴结和全身对病毒的免疫，建立一个delta32 CCR5突变的猿类模型。该策略是使用微生物70kd热休克蛋白（HSP70），刺激CC趋化因子的产生并作为佐剂。CCR5与hsp70连接的细胞外肽免疫可引起CCR5抗体和CC趋化因子。这将通过使用SIV包膜gp120和gag p27与特异性SIV靶向免疫相结合。用SIV-CCR5疫苗在恒河猴中通过直肠途径进行免疫，并与SIV-HSP70或CCR5-HSP70疫苗进行比较。在每次免疫前后，将在粘膜和全身区室监测广泛的先天性和适应性免疫反应。动物将在第三次免疫后4周用SIVmac 251进行挑战。24周内监测血浆病毒载量、CD4 v T细胞计数和IFN'y，随后处死动物，测定粘膜组织、淋巴结和脾脏中的病毒载量。这种新的免疫策略，旨在产生先天和适应性免疫，并针对病毒及其主要辅受体，可能被证明是预防或控制HIV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.