Restoring anti-viral immunity during HTLV-associated neuroinflammatory disease

描述：全球有2000万人感染HTLV-1，其中大多数人仍然是无症状携带者(ACS)，而少数人发展为ATL或HAM/TSP，这两种疾病都没有有效的治疗方法或疫苗。尽管细胞免疫反应强烈(主要针对病毒反式激活蛋白TAX)，但疾病病理生理的确切机制(S)仍未解决HAM/TSP患者高前病毒负荷的大问题。我们的初步研究表明，程序性死亡(PD)-1受体及其配体PD-L1是观察到的免疫细胞功能障碍导致病毒持续和疾病进展的潜在潜在因素，主要是在HAM/TSP患者。PD-1：PD-L1/PD-L2是免疫球蛋白超家族(IgSF)共信号分子的成员，与慢性病毒感染时CD8 T细胞耗竭有关。CTL-4：B7-1(CD80)/B7-2(CD86)、LAG-3：HL-DR、TIM-3：Galectin-9、2B4：CD48和BTLA CD160：Hvem在调节抗原特异性免疫应答中发挥重要作用。到目前为止，PD-1和CTLA-4通路已经得到了广泛的研究；针对这些通路的阻断抗体在癌症的发生中显示出临床上的好处。最近的进一步数据表明，同时阻断多个抑制性受体可能会改善基于T细胞的治疗，但需要进一步的研究来澄清每个受体-配体对的作用。此外，PD-1和CTLA-4在人类慢性病毒感染以及神经炎症性疾病(如HAM/TSP、神经艾滋病等)中的临床适用性仍有待测试。有趣的是，HTLV-1为两者提供了一个很好的模型，因此，我们发现研究关键抑制受体/配体在HTLV-1感染中的作用并联合阻断它们作为潜在的免疫治疗策略来恢复HAM/TSP患者的免疫细胞功能具有重要意义。虽然这种方法应该有助于恢复患者原有的抗病毒免疫功能，但激活新的CTL来模拟在ACS中发现的多克隆CD8 T细胞反应将是成功的HTLV相关疾病免疫治疗干预的关键。因此，我们建议系统地鉴定HTLV-1感染细胞呈递的T细胞表位，这些表位在沉默的携带者中定义保护性免疫，同时阻断抑制途径，以便完全恢复慢性感染患者的T细胞功能。旨在实现这些目标的具体目标是：1)调查免疫球蛋白SF负性调节因子的共表达模式，并制定阻断策略，以恢复HTLV-1患者队列中抗原特异性T细胞的多功能性和溶细胞潜能；2)对感染细胞上的MHC I类：肽复合体进行广泛的免疫蛋白质组学分析，通过对携带者和疾病患者进行比较免疫原性测试，确定最佳抗HTLV-1多克隆T细胞应答候选者(S)；以及3)在HTLV-1感染的人源化小鼠的背景下，评估利用新表位恢复免疫细胞功能和扩大细胞免疫应答的联合策略。。

DESCRIPTION: Worldwide, 20 million people are infected with HTLV-1, a majority of which remain asymptomatic carriers (ACs), while a few develop ATL or HAM/TSP with no effective treatment or vaccine for either disease state. The exact mechanism(s) of disease pathophysiology remain unresolved with a big question of high proviral load in HAM/TSP patients despite vigorous cellular immune response (primarily directed towards viral transactivator protein Tax)? Our initial studies implicated programmed death (PD)-1 receptor and its ligand, PD-L1 as potential underlying factors for observed immune cells' dysfunctions leading to viral persistence and disease progression, primarily in HAM/TSP patients. PD-1:PD-L1/PD-L2 are the members of immunoglobulin superfamily (IgSF) co-signaling molecules and have been linked with CD8 T-cell exhaustion during chronic viral infections. Several members of this family including CTL-4:B7-1(CD80)/B7-2(CD86), LAG-3:HLA-DR, Tim- 3:Galectin-9, 2B4:CD48, and BTLA CD160:HVEM play critical role in regulating antigen-specific immune responses. Thus far, PD-1 and CTLA-4 pathways have been extensively studied; and blocking antibodies against these have shown clinical benefit in the setting of cancer. Further recent data suggest that blocking multiple inhibitory receptors simultaneously may improve T-cell based therapies, but further studies are required to clarify the role of each receptor-ligand pair. Moreover, the clinical applicability of PD-1 and CTLA-4 remains to be tested with respect to human chronic viral infections as well as neuroinflammatory diseases, such as HAM/TSP, NeuroAIDS, etc. Interestingly, HTLV-1 provides a good model for both and thus, we find it significant to investigate the role of key inhibitory receptors/ligands in HTLV-1 infection and tes their combined blockade as potential immunotherapeutic strategy to restore immune cell functions in HAM/TSP patients. While this approach should help in restoring functions of pre-existing antiviral immunity in patients, activating new CTLs to mimic polyclonal CD8 T-cell response found in ACs will be the key for a successful immunotherapeutic intervention of HTLV-associated diseases. Therefore, we propose to systematically identify T-cell epitopes presented by HTLV-1-infected cells that define protective immunity in silent carriers alongside blocking inhibitory pathways in order to fully restore T-cell functions in chronically infected patients. Th Specific Aims to achieve these goals are to 1) Investigate co-expression patterns of IgSF negative regulators and devise a blockade strategy to restore polyfunctionality and cytolytic potential of antigen-specific T-cells in HTLV-1 patient cohorts; 2) Perform extensive immunoproteomics analyses of MHC Class I:peptide complexes on the infected cells, and identify best candidate(s) for anti-HTLV-1 polyclonal T-cell response by comparative immunogenicity testing in carriers versus diseased individuals; and 3) Evaluate the combined strategy of restoring immune cell functions along with the expansion of cellular immune response using neo-epitopes in the context of HTLV-1-infected humanized mice. .