Adjuvanted Epitope Vaccine to Target HIV Reservoirs

针对 HIV 病毒库的佐剂表位疫苗

• 批准号: 7001218
• 负责人: Michael A Murphey-Corb
• 金额: $ 54.91万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7001218
• 关键词: AIDS therapy; AIDS vaccines; Macaca mulatta; disease reservoirs; enzyme linked immunosorbent assay; helper T lymphocyte; immunomodulators; lung lavage; lymph nodes; mucosal immunity; polymerase chain reaction; simian AIDSs; simian immunodeficiency virus; vector vaccine; virus load; virus replication

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.

描述（由申请人提供）：与抗逆转录病毒药物（HAART）组合对HIV感染的治疗已被证明在HIV感染的临床管理中非常有效。不幸的是，Haart不会消除HIV，因为它似乎对病毒储层几乎没有影响。改善HIV-1感染治疗的最新策略已集中在免疫治疗干预上。然而，一种诱导HAART去除后长期控制病毒的疫苗方案需要将疫苗靶向病毒的产生来源。我们假设病毒生产的主要储层存在于粘膜组织中。因此，需要一种在粘膜中诱导有效T细胞反应的疫苗需要在HAART悬浮后提供对病毒的持续控制/清除率。我们将使用一种新型的表位定向的DNA疫苗与编码靶向粘膜组织的热比率大肠杆菌肠毒素LT的令人兴奋的新遗传佐剂结合使用的新型表位DNA疫苗在SIV：猕猴模型中检验这一假设。该疫苗编码7个免疫主导的SIV特异性CTL和3 T辅助表位，与高度免疫原性肝炎核心抗原（HBC）载体基因相关。包括多个保守的表位，以及诱导粘膜反应的佐剂，应能够控制HAART期间在储层中持续存在的各种病毒分离株。在AIM 1中，我们将测试HBC - ePitope DNA疫苗 + LT作为HAART治疗慢性SIV感染的辅助手段。 AIM 2将用于表征由治疗性DNA免疫引起的免疫反应，无论是在外围和直接在粘膜组织中。将在AIM 3中鉴定出持久病毒复制的病毒储存库。在CD4+和CD14+细胞中表达的SIV序列，来自肠系膜和外周淋巴结，肺灌洗，Jejunal层层次的肺液化和PBMC期间的肺lamina lamina propria和PBMC的均质和定量比较，均应进行定性和定量比较。药物停产后。可以在一年的随访中处死动物，以便可以类似地分析肝，脾脏，骨髓和中枢神经系统，以便可以鉴定出病毒产生的细胞和组织特异性储层。总之，这些研究都将定义慢性感染期间病毒持久性的性质，并确定一种有效的治疗方法。

项目成果

Therapeutic DNA vaccine induces broad T cell responses in the gut and sustained protection from viral rebound and AIDS in SIV-infected rhesus macaques.

• DOI: 10.1371/journal.pone.0033715
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Fuller DH;Rajakumar P;Che JW;Narendran A;Nyaundi J;Michael H;Yager EJ;Stagnar C;Wahlberg B;Taber R;Haynes JR;Cook FC;Ertl P;Tite J;Amedee AM;Murphey-Corb M
• 通讯作者: Murphey-Corb M