Immune Correlates of Protection Against SIVE

描述（由申请人提供）：尽管抗逆转录病毒治疗广泛使用，神经系统疾病仍然是与HIV感染相关的发病率和死亡率的重要因素。预防HIV感染的神经致病性进展的免疫学相关因素尚未被描述，但对宿主免疫所起的神经保护和神经退行性作用的理解是有效疫苗开发的核心。使用猿猴免疫缺陷病毒（SIV）模型的研究表明，CD8+淋巴细胞在急性感染期间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，体液免疫对预防SIVE的相对贡献仍然未知。本研究计划将使用神经毒性SIVsmmFGb模型专门研究中和抗体（nab）对脑病毒负荷和SIVE的影响。使用该模型，我们发现即使在接种后1个月（mpi）没有可测量的细胞介导应答，接种后3个月（mpi）具有可检测nAb应答的猕猴也能抵抗SIVE。我们假设nab在中和敏感的嗜巨噬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nab在急性感染期间补充细胞介导的对SIVE的保护，并在慢性感染期间限制CNS中病毒再激活的程度。为了验证这些假设，在Aim 1中，我们将在SIVsmmFGb感染的整个过程中，将血液和脑脊液中nab的数量和质量与脑病毒负荷和SIVE标志物联系起来，特别关注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升将与对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Aim 2中，我们将通过在SIVsmmFGb感染前消耗CD20+ B细胞并评估神经致病结果来确定体液免疫对SIVE发病机制的影响。我们假设，细胞免疫不佳的cd20缺失猕猴会由于nAb反应受损而发生SIVE，而nAb反应完整的未缺失猕猴会抵抗SIVE。在Aim 3中，我们将采用被动治疗方法来检测急性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的新生产生，并且SIVIG治疗的猕猴比对照组具有更低的脑病毒负荷和更长时间的抗SIVE。这些研究的结果将有助于衡量除了抗病毒CTL之外，在开发旨在预防艾滋病毒感染的众多和各种后遗症的疫苗中包括产生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.