Regulation of PD-1 as a strategy against chronic HIV-1 infection

调节 PD-1 作为对抗慢性 HIV-1 感染的策略

• 批准号: 8662701
• 负责人: LI HUANG
• 金额: $ 19.63万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-20 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662701
• 关键词: Acids; Affect; Animals; Antibodies; B-Lymphocytes; Biotin; Blocking Antibodies; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Cessation of life; Chimeric Proteins; Chronic; Dendritic Cells; Development; Drug Targeting; FDA approved; Family; Foundations; Goals; HIV; HIV-1; Human; Immune; Immune response; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Individual; Infection; Lead; Lymphocyte; Macaca; Modeling; Molecular Probes; Monoclonal Antibodies; Morbidity - disease rate; Pathway interactions; Peripheral Blood Mononuclear Cell; Photoaffinity Labels; Play; Program Effectiveness; Proteins; Regulation; Reporting; Role; SIV; Series; Small Interfering RNA; T memory cell; T-Cell Activation; T-Lymphocyte; Technology; Testing; Tissues; Triterpenes; Virus; Virus Diseases; analog; antiretroviral therapy; base; drug candidate; exhaust; exhaustion; improved; in vitro activity; macrophage; melanoma; mortality; novel therapeutic intervention; prevent; programs; public health relevance; receptor; screening; small molecule; success

DESCRIPTION (provided: This proposal is an R21 application entitled "Regulation of PD-1 as a strategy against chronic HIV-1 infection". The current antiretroviral therapy (ART) has shown tremendous success in reducing the mortality and morbidity of HIV-1 infected individuals. However, ART has failed to eradicate the virus since the virus is suppressed rather than truly eradicated. Programmed death 1 (PD-1) has emerged as a potential target to facilitate HIV eradication because it is associated with T cell exhaustion. PD-1 is an inhibitory immune- checkpoint receptor expressed on a variety of immune cells. PD-1 was shown to adversely hinder the immune responses to chronic viral infections, such as HIV-1 infections. Elevated PD-1 level positively correlates with T cell exhaustion and latently-infected HIV-1 in memory T cells. The ability of T cells to recover from exhaustion was shown to be inversely correlated with PD-1 level. Furthermore, animal studies indicated that anti-PD-1 antibody was well-tolerated and led to increased SIV-specific CD8 and CD4 T-cell functions and an improved survival in SIV-infected animals. Thus, targeting PD-1 to regulate immune responses is a promising strategy that can be developed into a novel therapeutic approach against chronic HIV-1 infection. Although there are antibodies and fusion proteins that can effectively modulate the function of PD-1, no small molecules have been reported to regulate PD-1 expression and function. Therefore, the goal of this study is to identify small molecules that can selectively suppress the expression of PD-1. The rationale of this study is that inhibition of PD-1 expression will prevent or rescue CD8+ T cells from exhaustion. In an initial screening, we discovered that triterpene derivatives, such as dihydrobetulinic acid (d-BA) and a d-BA derivative D9-1, could selectively suppress the PD-1 expression on human peripheral blood mononuclear cells at low micro molar concentrations without affecting T cell activation. Based on these encouraging preliminary results, we hypothesize that small molecules can be synthesized with the ability of selectively suppressing PD-1 expression and used to prevent or rescue T cells from exhaustion. The following two specific aims are proposed to test this hypothesis: (1) to obtain potent PD-1 suppressors through lead optimization based on our preliminary results; (2) to identify the target protein of the PD-1 suppressors using biotin-tagged molecular probe with photoaffinity labeling functionality. PD-1 is in the same family of inhibitory receptors such as CTLA-4. Ipilimumab, a CTLA-4 monoclonal antibody, was recently approved by FDA for anti-melanoma therapy. The effectiveness of PD-1 blockade was successfully demonstrated in a SIV/macaque model. Therefore, PD-1 is a valid drug target, and accomplishing the proposed studies will lay a foundation for further development of this class of small molecules as immunotherapeutic drug candidates for potential HIV-1 eradication.

描述（提供：本提案是一项R21申请，标题为“调节PD-1作为对抗慢性HIV-1感染的策略”。目前的抗逆转录病毒疗法（ART）在降低HIV-1感染者的死亡率和发病率方面取得了巨大成功。然而，ART未能根除病毒，因为病毒被抑制而不是真正根除。程序性死亡1（PD-1）已成为促进HIV根除的潜在靶点，因为它与T细胞耗竭有关。PD-1是一种在多种免疫细胞上表达的抑制性免疫检查点受体。PD-1被证明会不利地阻碍对慢性病毒感染（如HIV-1感染）的免疫应答。PD-1水平升高与记忆T细胞中的T细胞耗竭和潜伏感染HIV-1呈正相关。 T细胞从衰竭中恢复的能力与PD-1水平呈负相关。此外，动物研究表明，抗PD-1抗体耐受性良好，并导致SIV特异性CD 8和CD 4 T细胞功能增加，并改善SIV感染动物的存活率。因此，靶向PD-1来调节免疫反应是一种很有前途的策略，可以发展成为一种针对慢性HIV-1感染的新型治疗方法。虽然有抗体和融合蛋白可以有效地调节PD-1的功能，但还没有报道小分子可以调节PD-1的表达和功能。因此，本研究的目的是鉴定可以选择性抑制PD-1表达的小分子。本研究的基本原理是抑制PD-1表达将防止或拯救CD 8 + T细胞耗竭。在初步筛选中，我们发现三萜衍生物，如二氢桦木酸（d-BA）和d-BA衍生物D9-1，可以在低微摩尔浓度下选择性地抑制人外周血单核细胞上的PD-1表达而不影响T细胞活化。基于这些令人鼓舞的初步结果，我们假设可以合成具有选择性抑制PD-1表达的能力的小分子，并用于防止或拯救T细胞耗尽。我们提出了以下两个具体目标来验证这一假设：（1）基于我们的初步结果通过先导优化获得有效的PD-1抑制剂;（2）使用具有光亲和标记功能的生物素标记的分子探针来鉴定PD-1抑制剂的靶蛋白。PD-1与CTLA-4等抑制性受体属于同一家族。Ipilimumab是一种CTLA-4单克隆抗体，最近被FDA批准用于抗黑色素瘤治疗。在SIV/猕猴模型中成功证明了PD-1阻断的有效性。因此，PD-1是一个有效的药物靶点，完成拟议的研究将为进一步开发这类小分子作为潜在的HIV-1根除候选免疫药物奠定基础。