Immune Correlates of Protection Against SIVE

描述（由申请方提供）：尽管抗逆转录病毒治疗广泛使用，但神经系统疾病仍是HIV感染相关发病率和死亡率的重要原因。免疫学相关的保护对HIV感染的神经病理性进展的特点还没有，但宿主免疫所发挥的神经保护和神经退行性作用的理解是有效的疫苗开发的核心。使用猿猴免疫缺陷病毒（SIV）模型的研究表明，CD 8+淋巴细胞在急性感染期间可保护免受快速致死性SIV脑炎（SIVE）的侵害;然而，体液免疫在急性和慢性感染期间对SIVE保护的相对贡献仍然未知。该研究计划将使用神经毒性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）具有可检测的nAb应答的猕猴即使在3 mpi时不存在可测量的细胞介导的应答时也能抵抗SIVE。我们假设nAbs在CNS中特别有效，其中中和敏感的嗜巨噬细胞病毒占主导地位。此外，我们假设nAbs在急性感染期间补充细胞介导的抗SIVE保护，并在慢性感染期间限制CNS中病毒再活化的程度。为了检验这些假设，在目的1中，我们将在整个SIVsmmFGb感染过程中将血液和CSF中nAb的数量和质量与脑病毒负荷和SIVE标志物相关联，特别注意nAb对（1）自体病毒分离物和（2）巨噬细胞中病毒复制的影响。我们假设nAb升将与SIVE的保护相关，特别是在具有次优抗病毒细胞免疫的猕猴中。在目的2中，我们将通过在SIVsmmFGb感染前耗竭CD 20 + 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，CD 20耗竭的猕猴与次优的细胞免疫将发展SIVE由于受损的nAb反应，而非耗竭的猕猴与完整的nAb反应将抵制SIVE。在目的3中，我们将使用被动治疗方法来检查nAb在急性SIVsmmFGb感染期间对SIVE的影响。我们假设，被动治疗SIV免疫球蛋白（SIVIG）将促进从头生产的nAb，SIVIG治疗猕猴将有较低的脑病毒负荷和抵抗SIVE比对照组更长。这些研究的结果将有助于衡量在开发旨在预防HIV感染的众多和不同后遗症的疫苗时，除了抗病毒CTL之外，还包括产生nAb的方法的相关性。

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.