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HIV感染的疫苗策略，该策略基于“自然实验”，其中在具有纯合A32 CCR 5突变的受试者中发现了对HIV感染的抗性。具体目的是通过（a）阻断和下调参与原发性粘膜HIV感染的CCR 5辅助受体和（B）引发针对病毒的粘膜、区域淋巴结和全身免疫来开发delta 32 CCR 5突变的猿猴模型。该策略是使用微生物70 kD热休克蛋白（HSP 70），其刺激CC趋化因子的产生并作为佐剂起作用。用与HSP 70连接的CCR 5细胞外肽进行免疫，会引发针对CCR 5以及CC趋化因子的抗体。这将通过使用SIV包膜gp 120和gagp 27与特异性SIV靶向免疫结合。SIV-CCR 5疫苗的免疫将通过恒河猴的直肠途径进行，并与施用SIV-HSP 70或CCR 5-HSP 70的那些进行比较。在每次免疫之前和之后，将在粘膜和全身隔室中监测广泛的先天性和适应性免疫应答。动物将在第3次免疫后4周用SIVmac 251攻击。将监测其血浆病毒载量、CD 4 v T细胞计数和IFN-γ 24周，此时将处死动物并测定粘膜组织、淋巴结和脾脏中的病毒载量。这种新的免疫策略，旨在产生先天性和适应性免疫，并针对病毒及其主要辅助受体，可能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.