Adjuvanted Epitope Vaccine to Target HIV Reservoirs

描述(由申请人提供)：用抗逆转录病毒药物(HAART)联合治疗艾滋病毒感染已被证明在艾滋病毒感染的临床管理中非常有效。不幸的是，HAART不能根除艾滋病毒，因为它似乎对病毒库几乎没有影响。最近改进HIV-1感染治疗的战略侧重于免疫治疗干预。然而，在去除HAART后诱导病毒长期控制的疫苗方案需要将疫苗靶向病毒产生的源头。我们假设病毒产生的主要储存库存在于粘膜组织中。因此，在HAART暂停后，需要一种在粘膜中诱导强大T细胞反应的疫苗来提供对病毒的持续控制/清除。我们将在SIV：猕猴模型中使用一种新的表位导向的DNA疫苗和一种令人兴奋的新基因佐剂来测试这一假设，该佐剂编码以粘膜组织为靶标的不稳定的大肠杆菌肠毒素LT。该疫苗编码7个免疫显性SIV特异性CTL和3个与高免疫原性肝炎核心抗原(HBc)载体基因连锁的T辅助表位。包含多个保守的表位，加上一种诱导粘膜反应的佐剂，应该能够控制在HAART期间持续存在于水库中的不同病毒分离株。在目标1中，我们将测试HBc表位DNA疫苗+LT作为HAART的辅助治疗慢性SIV感染。目的2描述治疗性DNA免疫在外周和直接在粘膜组织中诱导的免疫反应。AIM 3将确定持续病毒复制的病毒库。治疗期间和停药后反弹期间，将定性和定量比较肠系膜和外周淋巴结、肺灌洗、空肠固有层和PBMC中CD4+和CD14+细胞表达的SIV序列。动物将在一年的随访中被处死，这样就可以对肝脏、脾、骨髓和中枢神经系统进行类似的分析，从而确定产生病毒的细胞和组织特异性储存库。总之，这些研究将确定慢性感染期间病毒持续的性质，并确定有效的治疗方法。

DESCRIPTION (provided by applicant): Treatment of HIV infection with a combination of antiretroviral drugs (HAART) has proven to be highly effective in the clinical management of HIV infection. Unfortunately, HAART does not eradicate HIV because it appears to have little effect on the viral reservoir. Recent strategies to improve treatment of HIV-1 infection have focused on immunotherapeutic intervention. However, a vaccine regimen that induces long-term control of virus after removal of HAART requires targeting the vaccine to the source of virus production. We hypothesize that the major reservoir of virus production resides in mucosal tissues. Therefore, a vaccine that induces potent T cell responses in the mucosa is required to provide persistent control/clearance of virus after suspension of HAART. We will test this hypothesis in the SIV:macaque model using a novel epitope-directed DNA vaccine combined with an exciting new genetic adjuvant encoding the heat-labile E. Coli enterotoxin LT that targets mucosal tissues. The vaccine encodes 7 immunodominant SIV-specific CTL and 3 T helper epitopes linked to a highly immunogenic hepatitis core antigen (HBc) carrier gene. The inclusion of multiple, conserved epitopes, together with an adjuvant that induces mucosal responses, should enable control of diverse viral isolates persisting in reservoirs during HAART. In Aim 1 we will test the HBc-epitope DNA vaccine + LT as an adjunct to HAART for therapy of chronic SIV infection. Aim 2 will be directed to characterizing the immune responses induced by therapeutic DNA immunization, both in the periphery and directly in the mucosal tissues. The viral reservoir for persistent viral replication will be identified in Aim 3. SIV sequences expressed in CD4+ and CD14+ cells from mesenteric and peripheral lymph nodes, lung lavage, jejunal lamina propria and in PBMC will be both qualitatively and quantitatively compared during therapy and during rebound after drug is discontinued. Animals will be sacrificed at one year of follow-up so that liver, spleen, bone marrow, and the central nervous system can be similarly analyzed so that the cellular and tissue-specific reservoirs of virus production can be identified. Together, these studies will both define the nature of viral persistence during chronic infection and identify an effective method of treatment.