Boosting anti-HIV immunity through manipulation of Tfh function.

通过操纵 Tfh 功能增强抗 HIV 免疫力。

• 批准号: 9272789
• 负责人: Elias K Haddad
• 金额: $ 54.63万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9272789
• 关键词: Adoptive Transfer; Affect; Anatomy; Anti-Retroviral Agents; Antibodies; Antibody Formation; Antibody Response; Autologous; B-Lymphocytes; Blood Circulation; CD8-Positive T-Lymphocytes; Cardiovascular Diseases; Cell Communication; Cell Compartmentation; Cell physiology; Cells; Chronic; Clinical; Cytokine Network Pathway; Data; Defect; Development; Disease; Exhibits; Functional disorder; Gene Expression Profile; Goals; Grant; HIV; HIV Antibodies; HIV Infections; HIV-1; Human; Humoral Immunities; Immune System Diseases; Immune System and Related Disorders; Immune response; Immune system; Immunity; Immunotherapeutic agent; Immunotherapy; Impairment; In Vitro; Individual; Infection; Inflammation; Injection of therapeutic agent; Interleukin-4; Interruption; Intervention; Lead; Ligands; Macaca; Macaca mulatta; Measurement; Mediating; Memory; Memory B-Lymphocyte; Metabolic; Modeling; Molecular Profiling; Output; PDCD1LG1 gene; Pathway interactions; Plasma; Play; Production; Quality of life; Recurrence; Regimen; Reporting; Rest; Role; SIV; Signal Transduction; T-Lymphocyte; Testing; Toxic effect; Vaccines; Viral; Viremia; Virus; Virus Replication; Work; adaptive immune response; antiretroviral therapy; base; cytokine; experimental study; high voltage electron microscopy; humanized mouse; immune activation; improved; in vivo; lymph nodes; mouse model; neutralizing antibody; novel; novel therapeutics; premature; prevent; public health relevance; receptor; receptor expression; reconstitution; response; viral rebound

DESCRIPTION (provided by applicant): Viral suppression in the majority of HIV infected subjects can only be achieved with ART. Despite the significant decrease in inflammation and immune activation following ART, people under ART still exhibit low levels of both these activities leading to significant immune dysfunction that is illustrated by the inability to generae and maintain T cell and B cell immunity. Furthermore, ART therapy induces long and short-term toxicities leading to cardiovascular diseases and other complications. We have recently reported a significant dysfunction in the memory CD4 compartment in virally suppressed individuals undergoing ART. We have also shown a similar defect in the memory B cell compartment with these cells dying prematurely and producing significantly lower levels of anti-HIV antibodies when compared to natural controllers. Even when treated in the first few weeks after infection, only a small percentage of HIV infected subjects are able to contain viremia upon cessation of ART. Whereas, the large majority of HIV infected individuals exhibit resurgence of viremia demonstrating the inability of the immune system to contain viral replication in the absence of ART. This provides a strong rationale to develop novel immunotherapies that aim at augmenting anti-HIV immunity in chronically infected individuals in the absence of ART with the purpose of achieving a functional cure. Thus the inability to achieve a functional immune response against HIV upon treatment interruption in virally suppressed subjects is a major problem. Thus, for the majority of HIV infected individuals (more than 85%), the goal of acquiring anti-HIV immunity in the absence of ART is only possible with the augmentation of adaptive immune responses. In this proposal we will study the underlying mechanisms that could be responsible for their defective immune response in an effort of moving closer towards achieving a functional cure. We will further work under the educated assumption that enhancing the CD4+Tfh/B cell axis is critical for attaining improved anti-HIV immunity.

描述（由申请人提供）：大多数HIV感染受试者中的病毒抑制只能通过ART实现。尽管ART后炎症和免疫活化显著减少，但接受ART的人仍然表现出低水平的这两种活性，导致显著的免疫功能障碍，这表现为不能产生和维持T细胞和B细胞免疫。此外，抗逆转录病毒疗法引起长期和短期毒性，导致心血管疾病和其他并发症。我们最近报道了一个显着的功能障碍，在记忆CD 4室在病毒抑制的个人接受ART。我们也显示了类似的缺陷，在记忆B细胞室与这些细胞过早死亡，产生显着较低水平的抗HIV抗体相比，自然控制器。即使在感染后的最初几周内进行治疗，也只有一小部分HIV感染受试者在停止ART后能够控制病毒血症。绝大多数HIV感染者表现出病毒血症的复发，这表明在没有ART的情况下免疫系统不能抑制病毒复制。在没有抗逆转录病毒疗法的情况下，慢性感染者的艾滋病毒免疫力，目的是实现功能性治愈。因此，在病毒抑制的受试者中，在治疗中断时不能实现针对HIV的功能性免疫应答是一个主要问题。因此，对于大多数HIV感染者（超过85%）来说，在没有ART的情况下获得抗HIV免疫力的目标只有在增强适应性免疫应答的情况下才有可能。在这项提案中，我们将研究可能导致其免疫反应缺陷的潜在机制，以努力更接近实现功能性治疗。我们将进一步工作的教育的假设下，增强CD 4 +Tfh/B细胞轴是至关重要的，以获得改善的抗HIV免疫力。

项目成果

Altered Memory Circulating T Follicular Helper-B Cell Interaction in Early Acute HIV Infection.

• DOI: 10.1371/journal.ppat.1005777
• 发表时间: 2016-07
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Muir R;Metcalf T;Tardif V;Takata H;Phanuphak N;Kroon E;Colby DJ;Trichavaroj R;Valcour V;Robb ML;Michael NL;Ananworanich J;Trautmann L;Haddad EK;RV254/SEARCH010 RV304/SEARCH 013 Study Groups
• 通讯作者: RV254/SEARCH010 RV304/SEARCH 013 Study Groups

The dysfunction of T follicular helper cells.

• DOI: 10.1097/coh.0000000000000095
• 发表时间: 2014-09
• 期刊: Current opinion in HIV and AIDS
• 影响因子: 4.1
• 作者: Cubas R;Perreau M
• 通讯作者: Perreau M