IMMUNOMODULATOR-MEDIATED ENHANCEMENT OF ANTI-HIV-SPECIFIC IMMUNE RESPONSE

免疫调节剂介导的抗 HIV 特异性免疫反应的增强

• 批准号: 8357102
• 负责人: Miguel Otero
• 金额: $ 7.82万
• 依托单位: UNIVERSIDAD CENTRAL DEL CARIBE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357102
• 关键词: Agonist; Antigens; Biomedical Research; C57BL/6 Mouse; Cells; Cervical; Clinic; DNA; Exhibits; Funding; Gagging; Grant; HIV; HIV Infections; Human; Imiquimod; Immune response; Immunization; Immunoglobulin A; Immunomodulators; Interferon Type II; Interferons; Lung; Measures; Mediating; Mucosal Immune Responses; Mucous Membrane; Mus; National Center for Research Resources; Patients; Persons; Play; Principal Investigator; Protocols documentation; Recombinants; Reporting; Research; Research Infrastructure; Resources; Role; Route; Secretory Immunoglobulin A; Serum; Source; T-Lymphocyte; Testing; United States National Institutes of Health; Vaccination; Vaccines; Vaccinia; Vaccinium; Vagina; Viremia; base; cost; enzyme linked immunospot assay; human TLR7 protein; mucosal site; response; sex; transmission process

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Mucosal transmission is the principal route of HIV infection. It has been shown that the mucosal early innate interferon response plays an important role against HIV infection. However, the mucosal immune response against HIV would be more effective if the neutralizing secretory immunoglobulins A and G response could be enhanced. It has been reported that highly exposed, persistently seronegative patients such as Gambian sex workers, and partners of HIV infected persons who have unprotected sexual relations exhibit higher Gag, Pol and Nef-specific T cell IFN-gamma responses in cervical mucosa, as compared to HIV-seropositive patients. Moreover, several groups have shown that Gag induces an HIV-specific T-cell and IgA immune responses at mucosal sites of lung and vaginal tract, besides that Gag, Nef, and Pol have been used in numerous mucosal immunization protocols. Therefore, the selection of Gag, Nef and Pol as antigens in combination with a mucosal immunization approach is expected to have a positive impact in the HIV-specific immune responses. DNA based vaccines are known to elicit both: cell- and humoral-mediated immune responses, however there is a need to increase the amplitude of their response in humans. On this project, we will determine the immunomodulatory effect of Imiquimod (a Toll-like receptor 7 agonist) in the enhancement of the HIV-specific immune response on a DNA vaccination platform, after vaccination of C57BL/6 mice. Cell- and humoral-mediated immune responses, as measured by ELISPOT and ICC analysis in these mice, will be correlated with control of viremia after qPCR analysis of serum from recombinant HIV-vaccinia infected mice. We hypothesize that Imiquimod, will enhance the HIV-gag, nef and pol specific mediated immune responses, after a DNA based mucosal immunization in mice. We therefore expect that these results could be moved easily and safely into the clinics, and therefore, could be tested in humans.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其他NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 粘液传播是艾滋病毒感染的主要途径。已经表明，粘膜早期先天性干扰素应答在抗HIV感染中起重要作用。然而，如果能够增强中和分泌型免疫球蛋白A和G应答，则针对HIV的粘膜免疫应答将更有效。据报道，与HIV血清阳性患者相比，高度暴露的持续血清阴性患者，如冈比亚性工作者和具有无保护性关系的HIV感染者的伴侣，在宫颈粘膜中表现出更高的Gag、Pol和Nef特异性T细胞IFN-γ应答。此外，除了Gag、Nef和Pol已用于许多粘膜免疫方案之外，几个研究组已经表明Gag在肺和阴道的粘膜部位诱导HIV特异性T细胞和伊加免疫应答。因此，选择Gag、Nef和Pol作为抗原与粘膜免疫方法组合预期在HIV特异性免疫应答中具有积极影响。已知基于DNA的疫苗引发细胞介导的和体液介导的免疫应答，然而需要增加它们在人类中的应答幅度。在这个项目中，我们将确定咪喹莫特（Toll样受体7激动剂）在DNA疫苗接种平台上增强HIV特异性免疫应答的免疫调节作用，接种C57 BL/6小鼠后。在这些小鼠中通过ELISPOT和ICC分析测量的细胞和体液介导的免疫应答将与来自重组HIV-牛痘感染小鼠的血清的qPCR分析后的病毒血症控制相关。我们假设咪喹莫特在小鼠中基于DNA的粘膜免疫后将增强HIV-gag、nef和pol特异性介导的免疫应答。因此，我们希望这些结果可以轻松安全地转移到诊所，因此可以在人体中进行测试。