Immune Correlates of Protection Against SIVE

预防 SIVE 的免疫相关性

• 批准号: 7391662
• 负责人: Susan V. Westmoreland
• 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 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391662
• 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，但神经系统疾病仍然对与 HIV 感染相关的发病率和死亡率产生重大影响。预防艾滋病毒感染神经病变进展的免疫学相关性尚未得到表征，但了解宿主免疫所发挥的神经保护和神经退行性作用对于有效开发疫苗至关重要。使用猿猴免疫缺陷病毒 (SIV) 模型的研究表明，CD8+ 淋巴细胞在急性感染期间可预防快速致命的 SIV 脑炎 (SIVE)；然而，在急性和慢性感染期间，体液免疫对于预防 SIVE 的相对贡献仍不清楚。该研究计划将使用神经毒力SIVsmmFGb模型专门研究中和抗体（nAbs）对脑病毒负荷和SIVE的影响。使用该模型，我们发现在接种后 1 个月 (mpi) 时具有可检测到的 nAb 反应的猕猴即使在 3 mpi 时没有可测量的细胞介导的反应，也能抵抗 SIVE。我们假设 nAb 在中枢神经系统中特别有效，其中中和敏感的巨噬细胞嗜性病毒占主导地位。此外，我们假设 nAb 在急性感染期间补充细胞介导的针对 SIVE 的保护，并限制慢性感染期间中枢神经系统病毒再激活的程度。为了检验这些假设，在目标 1 中，我们将在整个 SIVsmmFGb 感染过程中将血液和脑脊液中 nAb 的数量和质量与脑病毒负荷和 SIVE 标记物相关联，特别注意 nAb 对 (1) 自体病毒的影响分离株和(2)病毒在巨噬细胞中的复制。我们假设 nAb 升数与对 SIVE 的保护有关，特别是在抗病毒细胞免疫功能欠佳的猕猴中。在目标 2 中，我们将通过在 SIVsmmFGb 感染前耗尽 CD20+ B 细胞并评估神经病理结果来确定体液免疫对 SIVE 发病机制的影响。我们假设，细胞免疫功能欠佳的 CD20 耗尽的猕猴将因 nAb 反应受损而发展为 SIVE，而 nAb 反应完整的非耗尽猕猴将抵抗 SIVE。在目标 3 中，我们将使用被动治疗方法来检查急性 SIVsmmFGb 感染期间 nAb 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，并且经 SIVIG 治疗的猕猴将具有较低的脑病毒负荷，并且比对照组更长时间地抵抗 SIVE。这些研究的结果将有助于评估除了抗病毒 CTL 之外还包括生成 nAb 的方法在开发旨在预防 HIV 感染的众多不同后遗症的疫苗中的相关性。