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: 8166206
• 负责人: Miguel Otero
• 金额: $ 7.9万
• 依托单位: UNIVERSIDAD CENTRAL DEL CARIBE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8166206
• 关键词: Antigens; Cells; Cervical; Clinic; Computer Retrieval of Information on Scientific Projects Database; DNA; Exhibits; Funding; Gagging; Grant; HIV; HIV Infections; HLA-A2.1; Haplotypes; Human; Immune response; Immunization; Immunoglobulin A; Immunologic Adjuvants; Immunomodulators; Influenza; Institution; Interferon Type II; Interferons; Laboratories; Lung; Malignant Neoplasms; Measures; Mediating; Mucosal Immune Responses; Mucous Membrane; Mus; North America; Pathway interactions; Patients; Persons; Play; Protocols documentation; Reporting; Research; Research Personnel; Resources; Role; Route; Secretory Immunoglobulin A; Serum; Source; T-Lymphocyte; Testing; Transgenic Mice; United States National Institutes of Health; Vaccination; Vaccines; Vaccinia; Vagina; Viremia; base; clinical application; enzyme linked immunospot assay; in vivo Model; mucosal site; respiratory; response; sex; transmission process

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 [3]. 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 [4], besides that Gag [5], [6], [7], [8], Nef [8] and Pol [8] 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 PAI (a polyantigenic immunopotentiator consisting of a mixture of influenza and respiratory vaccines that was proven to have anti-cancer and anti-HIV activities) in the enhancement of the HIV-specific immune response on a DNA vaccination platform, after vaccination of humanized HLA-A2.transgenic 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 pseudotyped vaccinia infected mice. We hypothesize that the Polyantigenic Immunomodulator, previously tested in our laboratory, will enhance the HIV-gag, nef and pol specific mediated immune responses, after a DNA based mucosal immunization in mice. Moreover, the facts that humanized HLA-A2.1 mice, which possess the most common human haplotype in North America, will be used as the in vivo model, and that PAI is formulated from components currently used in humans; will build a pathway towards a clinical application of this project. We therefore expect that these results could be moved easily and safely into the clinics, and therefore, could be tested in humans.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 粘膜传播是HIV感染的主要途径。已经表明，粘膜早期的先天干扰素反应对HIV感染起着重要作用。但是，如果可以增强中和中和中和中和中和中和的分泌免疫球蛋白A和G反应，则对HIV的粘膜免疫反应将更加有效。据报道，与HIV阳性患者相比，诸如冈比亚性工作者之类的高度暴露，持续的血清症患者，例如冈比亚性工作者，以及没有受保护性关系的艾滋病毒感染者的伴侣表现出较高的GAG，POL和NEF特异性T细胞IFN-GAMMA反应，与HIV粘膜患者相比[3]。此外，几个组表明，除了GAG [5]，[6]，[7]，[8]，NEF [8]，NEF [8]和POL [8]和POL [8]和POL [8]除了在众多的粘膜免疫协议中使用了GAG [4]。因此，预计将GAG，NEF和POL作为抗原与粘膜免疫方法结合使用将对HIV特异性免疫反应产生积极影响。已知基于DNA的疫苗同时引起：细胞和体液介导的免疫反应，但是有必要增加其在人类中反应的幅度。在这个项目上，我们将确定PAI（一种由流感和呼吸疫苗混合物组成的PAI的免疫调节作用，证明是在HIV特异性免疫反应上对DNA疫苗平台的增强，这些疫苗在DNA疫苗平台上具有抗癌和抗HIV活性。通过ELISPOT和ICC分析在这些小鼠中测量的细胞和体液介导的免疫反应将与对病毒血症的控制相关。我们假设在小鼠中基于DNA的粘膜免疫后，先前在我们的实验室中测试的多抗性免疫调节剂将增强HIV-GAG，NEF和POL特异性介导的免疫反应。此外，拥有北美最常见的人类单倍型的HLA-A2.1小鼠人性化的事实将被用作体内模型，并且PAI是由当前在人类中使用的组件制成的。将建立通往该项目的临床应用的途径。因此，我们希望这些结果可以轻松，安全地进入诊所，因此可以在人类中进行测试。