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：该提案是一份R21申请，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在降低艾滋病毒-1感染者的死亡率和发病率方面取得了巨大成功。然而，抗逆转录病毒疗法未能根除该病毒，因为病毒只是受到抑制，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细胞衰竭有关。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被证明对慢性病毒感染（如HIV-1感染）的免疫反应有不利影响。记忆T细胞中PD-1水平升高与T细胞衰竭和潜伏感染HIV-1呈正相关。