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

基本信息

批准号：
8573404
负责人：
Miguel Otero
金额：
$ 12.24万
依托单位：
UNIVERSIDAD CENTRAL DEL CARIBE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2017-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8573404
关键词：
Acquired Immunodeficiency Syndrome Adjuvant Affect Animals Antibiotics Antibodies Antigens Antiviral Agents Area Bacterial Vaccines Biological Assay Biomedical Research CD3 Antigens CD4 Positive T Lymphocytes CD44 gene CD8B1 gene CMV promoter Cells Cervical Characteristics Clinic Cloning Code Color DNA DNA Vaccines Data Correlations Development Disease Drug Formulations Effectiveness Enzyme-Linked Immunosorbent Assay Epitopes Exhibits Exposure to Flow Cytometry Fluorescein-5-isothiocyanate Frequencies Future Gagging Genes Goals HIV HIV Antigens HIV Infections HIV-1 HLA-A2 Antigen HLA-A2.1 Haplotypes Health Care Costs Hemagglutinin Hemorrhage Human IgE IgG1 Immune response Immune system Immunization Immunoglobulin A Immunoglobulin G Immunologic Adjuvants Immunologic Memory Immunomodulators Individual Influenza Influenza A virus Injection of therapeutic agent Instruction Interferon Type II Interferons Interleukin-10 Interleukin-2 Interleukin-4 Interleukin-6 Intraperitoneal Injections Kanamycin Resistance Laboratories Lung MHC Class I Genes Maps Measures Mediating Memory Monitor Mucosal Immune Responses Mucous Membrane Mus North America Ovary Pathway interactions Patients Peptide Library Peptides Persons Pilot Projects Plasmids Play Polyadenylation Population Decreases Process Proliferation Marker Property Protein Secretion Proteins Protocols documentation Public Health Quality of life Reagent Recombinant Proteins Reporting Role Route SELL gene Saliva Secretory Immunoglobulin A Serum Services Signal Transduction Site Spleen Staining method Stains Stimulus T-Cell Activation T-Lymphocyte TNF gene Testing Toll-like receptors Transgenic Mice Vaccination Vaccines Vaccinia Vaccinia virus Vaccinium Vagina Viral Viral Genes Viral Load result Viremia Virus arm base bovine growth hormone cell mediated immune response clinical application cytokine design enzyme linked immunospot assay expression cloning granzyme B improved in vivo Model long term memory magnetic beads mucosal site plasmid DNA programs recombinant peptide repository research study respiratory response sex tool transmission process vaccine evaluation vaginal fluid vector

项目摘要

Immunomodulator-Mediated Enhancement of Anti-HIV-Specific Immune Response 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 HlV-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 anticancer 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 HlV-gag, nef and pol specific mediated immune responses, after a DNA based mucosal immunization in mice. Moreover, the facts that humanized HI_A-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.

免疫调节剂介导的抗HIV特异性免疫反应增强粘膜传播是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HLV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和HLV粘膜粘膜中的HIV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[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的疫苗既引起：细胞和体液介导的免疫反应，但是需要增加其人类反应的幅度。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（一种多抗性免疫量）在增强HIV特异性免疫反应在DNA疫苗平台上的抗癌和抗HIV活性的混合物，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HLV-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人源化HI_A-A-A2.1小鼠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。