Adjuvanted Epitope Vaccine to Target HIV Reservoirs

描述（由申请人提供）：结合抗逆转录病毒药物（HAART）治疗HIV感染已被证明在HIV感染的临床管理中是非常有效的。不幸的是，HAART并不能根除艾滋病毒，因为它似乎对病毒库几乎没有影响。最近改善HIV-1感染治疗的策略集中在免疫治疗干预上。然而，在清除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来源。我们假设病毒产生的主要储存库位于粘膜组织中。因此，需要一种能在粘膜中诱导强效T细胞反应的疫苗，以便在HAART暂停治疗后持续控制/清除病毒。我们将在SIV：猕猴模型中测试这一假设，使用一种新的表位导向DNA疫苗，结合一种令人兴奋的新遗传佐剂，编码针对粘膜组织的热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）载体基因相关的T辅助表位。包含多个保守的表位，以及诱导粘膜反应的佐剂，应该能够控制在HAART期间持续存在于库中的多种病毒分离株。在Aim 1中，我们将测试hhbv表位DNA疫苗+ LT作为HAART治疗慢性SIV感染的辅助疗法。目的2将直接描述治疗性DNA免疫诱导的免疫反应，包括外周和直接在粘膜组织中。持续病毒复制的病毒库将在Aim 3中确定。SIV序列在肠系膜和外周淋巴结、肺灌洗、空肠固有层和PBMC的CD4+和CD14+细胞中表达，将在治疗期间和停药后反弹期间进行定性和定量比较。动物将在一年的随访中被处死，以便对肝脏、脾脏、骨髓和中枢神经系统进行类似的分析，从而确定细胞和组织特异性的病毒产生库。总之，这些研究将确定慢性感染期间病毒持久性的性质，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.