Immune Correlates of Protection Against SIVE

预防 SIVE 的免疫相关性

基本信息

批准号：
7195766
负责人：
Shawn Patrick O'Neil
金额：
$ 59.05万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-01 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7195766
关键词：
AIDS Dementia Complex AIDS Vaccines Acquired Immunodeficiency Syndrome Acute Address Affect Alkaline Phosphatase Am 80 Anemia Anesthesia procedures Animals Antibodies Antibody Formation Antiviral Agents Attention Autologous Automobile Driving Autopsy B-Lymphocytes Biological Assay Blood Blood - brain barrier anatomy Brain CCL2 gene CD4 Lymphocyte Count CD8-Positive T-Lymphocytes CD8B1 gene Cells Cellular Immunity Chronic Condition Confusion Control Groups Cytotoxic T-Lymphocytes Data Detection Development Disease Progression Dose Drug Kinetics Encephalitis End Point Environment Evolution Generations Globulins HIV HIV Infections HIV encephalitis Hand Highly Active Antiretroviral Therapy Humoral Immunities Immune Immune Sera Immune response Immunity Immunoglobulins Immunotherapy Impairment In Vitro Infection Infection prevention Lymphocyte MS4A1 gene Macaca Measurable Measurement Measures Mediating Methods Modeling Modification Molecular Cloning Monitor Monkeys Monoclonal Antibodies Morbidity - disease rate Mus Nerve Degeneration Neurologic Neuropathogenesis Numbers Outcome Pathogenesis Patients Pattern Peripheral Blood Mononuclear Cell Plasma Play Preparation Primates Principal Investigator Process Production Published Comment Rate Relative (related person)Reporter Reporting Research Research Personnel Research Proposals Resources Risk Role Role playing therapy SIV SIV encephalitis Serum Severities Sindbis Virus Specimen Statistically Significant Study Section Subfamily lentivirinae Suggestion T-Lymphocyte Testing Text Time Treatment Efficacy Vaccine Design Vaccines Variant Viral Viral Antibodies Virus Virus Diseases Virus Replication Week West Nile virus base cell mediated immune response cohort day design experience immunoprophylaxis improved in vivo interest macrophage monocyte mortality nervous system disorder neutralizing antibody pandemic disease prevent programs prototype research study response simian human immunodeficiency virus stressor vaccine development

项目摘要

DESCRIPTION (provided by applicant): Despite widespread use of anti-retro viral therapy, neurological disorders continue to contribute significantly to the morbidity and mortality associated with HIV infection. The immunological correlates of protection against neuropathogenic progression of HIV infection have not been characterized, but an understanding of the neuroprotective and neurodegenerative roles played by host immunity is central to effective vaccine development. Studies using the simian immunodeficiency virus (SIV) model have shown that CD8+ lymphocytes protect against rapidly fatal SIV encephalitis (SIVE) during acute infection; however, the relative contribution of humoral immunity to protection against SIVE during acute and chronic infection remains unknown. This research program will use the neurovirulent SIVsmmFGb model to specifically investigate the effects of neutralizing antibodies (nAbs) on brain virus burden and SIVE. Using this model, we have found that macaques with detectable nAb responses at 1 month post inoculation (mpi) resist SIVE even in the absence of measurable cell-mediated responses at 3 mpi. We hypothesize that nAbs are particularly effective in the CNS, where neutralization-sensitive macrophage-tropic viruses predominate. Furthermore, we hypothesize that nAbs supplement cell-mediated protection against SIVE during acute infection and limit the extent of viral reactivation in the CNS during chronic infection. To test these hypotheses, in Aim 1 we will correlate the magnitude and quality of nAbs in blood and CSF with brain virus burden and markers of SIVE throughout the course of SIVsmmFGb infection, paying particular attention to the effect of nAbs on (1) autologous virus isolates and on (2) virus replication in macrophages. We hypothesize that nAb liters will be correlated with protection against SIVE, particularly in macaques with suboptimal antiviral cellular immunity. In Aim 2, we will determine the impact of humoral immunity on SIVE pathogenesis by depleting CD20+ B cells before SIVsmmFGb infection and evaluating the neuropathogenic outcome. We hypothesize that CD20-depleted macaques with suboptimal cellular immunity will develop SIVE due to impaired nAb responses, while non-depleted macaques with intact nAb responses will resist SIVE. In Aim 3, we will use a passive therapy approach to examine the effect of nAbs on SIVE during acute SIVsmmFGb infection. We hypothesize that passive therapy with SIV-immune globulin (SIVIG) will promote de novo production of nAbs, and that SIVIG-treated macaques will have lower brain virus burdens and resist SIVE longer than controls. The results of these studies will help gauge the relevance of including methods to generate nAbs in addition to antiviral CTL in the development of vaccines designed to protect against the numerous and diverse sequelae of HIV infection.

描述（由申请人提供）：尽管广泛使用了抗雷特罗病毒疗法，但神经系统疾病仍在继续对与HIV感染相关的发病率和死亡率产生重大贡献。尚未表征针对HIV感染的神经病进展的免疫学相关性，但宿主免疫对神经保护作用和神经退行性作用的理解对于有效的疫苗发育至关重要。急性感染期间，使用Simian免疫缺陷病毒（SIV）模型的研究表明，CD8+淋巴细胞可以预防快速致命的SIV脑炎（SIVE）。然而，在急性和慢性感染期间，体液免疫对保护SIVE的相对贡献仍然未知。该研究计划将使用神经毒性SIVSMMFGB模型来专门研究中和抗体（NABS）对脑病毒负担和SIVE的影响。使用此模型，我们发现在接种后1个月（MPI）在3 MPI处没有可测量的细胞介导的响应的情况下，在接种后1个月内具有可检测的NAB响应的猕猴。我们假设NAB在中和中和敏感的巨噬细胞 - 循环病毒占主导地位的CNS中特别有效。此外，我们假设NABS补充了急性感染期间细胞介导的对SIVE的保护，并限制了慢性感染期间中枢神经系统病毒重新激活的程度。为了检验这些假设，在AIM 1中，我们将在SIVSMMFGB感染过程中将血液和CSF中NABS的大小和质量与脑病毒负担以及Sive的标记相关联，并特别注意Nabs对（1）自体病毒分离株以及（2）在（2）遗传噬菌体中的病毒复制的影响。我们假设NAB升与防止SIVE的保护相关，尤其是在具有次优的抗病毒细胞免疫的猕猴中。在AIM 2中，我们将通过在SIVSMMFGB感染前耗尽CD20+ B细胞来确定体液免疫对SIVE发病机理的影响，并评估神经病的结果。我们假设具有次优的细胞免疫的CD20滞后猕猴会因NAB响应受损而发展起来，而具有完整的NAB响应的不耗尽的猕猴将抵抗。在AIM 3中，我们将使用一种被动疗法方法来检查NABS对急性SIVSMMFGB感染期间Sive的影响。我们假设用SIV-免疫球蛋白（SIVIG）被动疗法将促进NABS的从头产生，并且SIVIG治疗的猕猴将具有较低的脑病毒负担和耐药性比对照更长。这些研究的结果将有助于衡量包括抗病毒CTL除了开发旨在防止HIV感染的众多和多样化的后遗症的疫苗中，除了抗病毒CTL外产生NAB的相关性。