Mechanisms of mucosal protection by HPV-SIV and gp96-lg-SIV vaccines

描述（由申请人提供）：在过去的几年中，我们已经开发了两种新的，非传统的疫苗策略，产生强大的粘膜免疫SIV抗原。这两种疫苗策略基于递送SIV-cDNA的人乳头瘤病毒（命名为HPV-SIV）和分泌免疫原性伴侣蛋白-gp 96- Ig-SIV-肽-复合物的HEK 293-细胞（命名为gp 96-Ig-SIV）。这些疫苗通过不同的途径施用，并通过不同的分子和细胞机制产生粘膜免疫应答。不同的分子机制意味着不同的转录和信号通路的激活，并可能产生不同程度的保护阴道SIV的挑战。将两种疫苗激活的途径与对SIV攻击的免疫应答和疾病保护相关联，将提供如何最好地联合收割机结合两种疫苗策略的信息，以在必要时有效地保护免受SIV疾病。假设1：由HPV-SIV和gp 96-lg SIV产生的粘膜免疫激活不同的分子和细胞机制，其进而通过不同的转录和信号传导途径差异地激活粘膜免疫的各种组分。粘膜中的不同免疫应答将转化为不同程度的保护，以免受SIV阴道攻击。假设二：HPV-SIV和gp 96-lg-SIV疫苗接种的组合将通过组合不同转录和信号传导途径的激活而协同产生粘膜免疫，从而产生具有增加的抵抗阴道SIV攻击的能力的全面粘膜免疫。这些假设将在以下具体的施舍中得到检验：1。用HPV-SIV和gp 96-lg-SIV接种恒河猴，并确定阴道、引流淋巴结和全身的免疫应答、转录谱和信号通路。2.通过阴道途径用SIV攻击未感染和接种疫苗的猕猴，并确定对病毒的免疫应答和在病毒血症前的蚀食期对免疫的病毒应答。3.确定两种疫苗单独和组合在SIV保护SIV感染中的有效性，并与粘液屏障功能、免疫应答、转录和蛋白质组学谱相关。 公共卫生相关性：该申请将研究两种创新的SIV疫苗，已知它们在包括女性生殖道在内的粘膜部位产生免疫应答。除免疫学试验外，还将通过基因组学和蛋白质组学分析来分析生殖道中的疫苗活性，并将其与阴道SIV攻毒保护相关。两种疫苗的组合提供了粘膜中全面免疫激活的潜力，从而提供对SIV感染的增强的抵抗力。

DESCRIPTION (provided by applicant): During the last several years we have developed two novel, unconventional vaccine strategies generating powerful mucosal immunity to SIV antigens. The two vaccine strategies are based on human papilloma virus delivering SIV-cDNAs, designated HPV-SIV, and on HEK293-cells secreting immunogenic chaperone-gp96- Ig-SIV-peptide-complexes, designated gp96-lg-SIV. The vaccines are administered by different routes and generate mucosal immune responses by different molecular and cellular mechanisms. Different molecular mechanisms imply activation of different transcriptional and signaling pathways and may generate different degrees of protection against vaginal SIV challenge. Correlating the pathways activated by the two vaccines with immune response to SIV challenge and protection from disease will provide the information how best to combine the two vaccine strategies, if necessary, for effective protection from SIV disease. Hypothesis 1: Mucosal immunity generated by HPV-SIV and gp96-lg SIV activate different molecular and cellular mechanisms which, in turn, differentially activate the various components of mucosal immunity through different transcriptional and signaling pathways. Differential immune responses in the mucosa will translate to different degrees of protection from vaginal challenge with SIV. Hypothesis 2: Combination of HPV-SIV and gp96-lg-SIV vaccination will synergize in generating mucosal immunity by combining the activation of different transcriptional and signaling pathways thereby generating comprehensive mucosal immunity with increased power to resist vaginal SIV challenge. These hypotheses will be tested in the following specific alms: 1. Vaccinate Rhesus macaques with HPV-SIV and with gp96-lg-SIV and determine the immune response, transcriptional profiles and signaling pathways in the vagina, draining lymph nodes and systemically. 2. Challenge naive and vaccinated macaques with SIV by the vaginal route and determine immune response to the virus and viral responses to immunity during the eclipse period prior to viremia. 3. Determine the effectiveness of the two vaccines singly and in combination in SIV protection SIV infection and correlate with mucus barrier function, immune responses, transcriptional and proteomic profiles. PUBLIC HEALTH RELEVANCE: This application will study two innovative SIV vaccines that are known to generate immune responses at mucosal sites including the female genital tract. Vaccine activity in the genital tract will be analyzed by genomic and proteomic analysis in addition to immunological assays and correlated with protection from vaginal SIV challenge. The combination of the two vaccines offers the potential of comprehensive immune activation in the mucosa providing enhanced resistance to SIV infection.