Immune Correlates of Protection Against SIVE

预防 SIVE 的免疫相关性

• 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
• 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

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)：尽管广泛使用抗逆转录病毒疗法，但神经疾病继续显著增加与艾滋病毒感染相关的发病率和死亡率。防止HIV感染的神经致病进展的免疫学相关性尚未确定，但了解宿主免疫所起的神经保护和神经退化作用是有效疫苗开发的核心。使用猴免疫缺陷病毒(SIV)模型的研究表明，CD8+淋巴细胞在急性感染期间对快速致死性SIV脑炎(SIVE)具有保护作用；但在急性和慢性感染期间，体液免疫对SIVE保护作用的相对贡献尚不清楚。本研究计划将使用神经毒力SIVsmmFGb模型来具体研究中和抗体(NAB)对脑病毒负荷和SIVE的影响。利用这个模型，我们发现，在接种后1个月(MPI)有可检测到NAB反应的猕猴，即使在3MPI时没有可测量的细胞中介反应，也能抵抗SIVE。我们假设nabs在中和敏感的巨噬细胞嗜性病毒占主导地位的中枢神经系统中特别有效。此外，我们假设，在急性感染期间，NABS补充了对SIVE的细胞介导的保护，并在慢性感染期间限制了病毒在中枢神经系统中的重新激活程度。为了验证这些假设，在目标1中，我们将在SIVsmmFGb感染过程中将血液和脑脊液中NABS的数量和质量与脑病毒载量和SIVE标志物相关联，特别关注NABS对(1)自体病毒分离和(2)巨噬细胞中病毒复制的影响。我们假设，NAB滴度将与对SIVE的保护相关，特别是在具有次优抗病毒细胞免疫力的猕猴中。在目标2中，我们将通过在SIVsmmFGb感染前清除CD20+B细胞和评估神经致病结局来确定体液免疫在SIVE发病中的作用。我们假设，细胞免疫功能不佳的CD20耗竭猕猴将由于NAB反应受损而发生SIVE，而NAB反应完整的非耗竭猕猴将抵抗SIVE。在目标3中，我们将使用被动治疗的方法来检测NABS在急性SIVsmmFGb感染期间对SIVE的影响。我们假设，SIV免疫球蛋白(SIVIG)的被动治疗将促进NAB的从头产生，并且SIVIG治疗的猕猴将比对照组具有更低的脑病毒负担和更长的SIVE抵抗时间。这些研究的结果将有助于衡量在开发旨在预防艾滋病毒感染的众多和多样化后遗症的疫苗时，除了抗病毒CTL之外还包括产生NAB的方法的相关性。