Adjuvanted Epitope Vaccine to Target HIV Reservoirs

描述（由申请人提供）：抗逆转录病毒药物（HAART）联合治疗HIV感染已被证明在HIV感染的临床管理中非常有效。不幸的是，HAART并不能根除HIV，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干预上。然而，在去除HAART后诱导长期控制病毒的疫苗方案需要将疫苗靶向病毒产生源。我们假设病毒产生的主要储存库存在于粘膜组织中。因此，需要一种在粘膜中诱导有效T细胞应答的疫苗，以在HAART混悬液后提供持久的病毒控制/清除。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的DNA疫苗结合一种令人兴奋的编码热不稳定E。靶向粘膜组织的大肠杆菌肠毒素LT。该疫苗编码7个免疫显性SIV特异性CTL和3个辅助性T细胞表位，与高免疫原性肝炎核心抗原（HBc）载体基因相连。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HAART期间在储库中持续存在的不同病毒分离株。目的1：检测HBc-表位DNA疫苗+LT作为HAART辅助治疗慢性SIV感染的效果。目的2将针对表征由治疗性DNA免疫诱导的免疫应答，在外周和直接在粘膜组织中。持续病毒复制的病毒储库将在目标3中确定。在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、肺灌洗液、空肠固有层的CD4+和CD14+细胞以及PBMC中表达的SIV序列。将在随访1年时处死动物，以便对肝脏、脾脏、骨髓和中枢神经系统进行类似分析，从而可以鉴定病毒产生的细胞和组织特异性储库。这些研究将共同定义慢性感染期间病毒持续存在的性质，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.