The Role of the Immune Response in Controlling the Size of the HIV Reservoir.

免疫反应在控制艾滋病病毒库大小中的作用。

• 批准号: 8210252
• 负责人: Una T O'Doherty
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8210252
• 关键词: Acquired Immunodeficiency Syndrome; Antiviral Therapy; Biological Assay; CD4 Positive T Lymphocytes; CD8B1 gene; Categories; Cell Cycle; Cells; Chronic; Cytolysis; Cytotoxic T-Lymphocytes; DNA; Data; Frequencies; Future; Goals; Grant; HIV; HIV Infections; Highly Active Antiretroviral Therapy; Immune; Immune response; In Vitro; Individual; Infection; Investigation; Lead; Literature; Lymphocyte Function; Measures; Monitor; Morbidity - disease rate; Patients; Proteins; Proviruses; RNA; Research; Resistance; Rest; Role; Secondary to; T-Lymphocyte; Testing; Time; Viral; Viral Load result; Virus; cell type; exhaustion; in vitro Model; in vivo; mortality; pressure; protein expression; research study

DESCRIPTION (provided by applicant): HIV-infected individuals accumulate a reservoir of treatment-resistant, latently infected resting CD4+ T cells. A special category of HIV infected individuals called elite suppressors have undetectable viral loads in the absence of highly active antiretroviral therapy (HAART) and have a smaller HIV reservoir. There is compelling evidence that elite suppressors (ES) have higher functioning CTL activity against HIV than treated and untreated chronic progressors. Our recent data provide evidence that CTL in ES have activity against latently infected resting CD4+ T cells in vivo. Specifically, we demonstrate for the first time that ES patients have dramatically lower levels of integrated HIV DNA and a relatively large excess of unintegrated HIV DNA compared to HAART patients. This is consistent with CTL pressure since HIV proteins are expressed more efficiently from integrated compared to unintegrated HIV DNA. In addition, we have preliminary data that latently infected resting CD4+ T cells express HIV proteins but do not permit spreading infection and thus should be susceptible to CTL pressure. At the same time, we show with our in vitro model of latency that CTL have activity against latently infected resting CD4+ T cells. Thus, the range of CTL targets is greater than previously thought since it appears that latently infected cells can be targets of CTL. In this application, we plan to test for further evidence of CTL pressure by assessing the frequency of HIV RNA+ cells among resting CD4+ T cells in ES vs HAART patients. We expect the frequency of HIV RNA+ cells normalized to integration to be lower in ES because we expect the majority of HIV RNA+ cells will express protein and be subjected to CTL lysis. Finally, we will determine if integration levels increase over time (as suggested by our preliminary data) in all or a subset of ES and if an increase in integration levels correlates with a loss of CTL function in ES. We also consider the alternate hypothesis that integration levels may increase over time in ES because defective proviruses accumulate. PUBLIC HEALTH RELEVANCE: A special category of HIV infected individuals, called elite suppressors, control HIV viral load to undetectable levels in the absence of antiviral therapy. The proposed experiments investigate the mechanism behind the ability of elite suppressors to maintain a smaller reservoir. Our studies suggest that elite suppressors have immune activity against treatment resistant reservoir cells and may lead to future therapies that harness the immune response to reduce reservoir size in patients receiving antiviral therapy.

描述（由申请方提供）：HIV感染个体积累了一个耐药、潜伏感染的静息CD4+ T细胞库。一种特殊类别的HIV感染者称为精英抑制者，在没有高效抗逆转录病毒治疗（HAART）的情况下，病毒载量无法检测到，并且HIV储存量较小。有令人信服的证据表明，精英抑制（ES）具有更高的功能CTL活性对艾滋病毒比治疗和未治疗的慢性进展。我们最近的数据提供了证据，CTL在ES细胞对潜伏感染的静息CD4+ T细胞在体内的活动。具体来说，我们首次证明，ES患者有显着较低水平的整合的HIV DNA和相对较大的过量的未整合的HIV DNA相比，HAART患者。这与CTL压力一致，因为与未整合的HIV DNA相比，整合的HIV DNA更有效地表达HIV蛋白。此外，我们有初步数据表明，潜伏感染的静息CD4+ T细胞表达HIV蛋白，但不允许传播感染，因此应该对CTL压力敏感。同时，我们用我们的体外潜伏模型表明CTL对潜伏感染的静息CD4+ T细胞具有活性。因此，CTL靶的范围比以前认为的更大，因为似乎潜伏感染的细胞可以是CTL的靶。在本申请中，我们计划通过评估ES与HAART患者中静息CD4+ T细胞中HIV RNA+细胞的频率来测试CTL压力的进一步证据。我们预期在ES中归一化为整合的HIV RNA+细胞的频率较低，因为我们预期大多数HIV RNA+细胞将表达蛋白质并进行CTL裂解。最后，我们将确定整合水平是否随时间增加（如我们的初步数据所示）在所有或一个子集的ES，如果在整合水平的增加与CTL功能的丧失ES。我们还考虑了另一种假设，即整合水平可能会随着时间的推移在ES，因为有缺陷的前病毒积累。 公共卫生关系：一类特殊的HIV感染者，称为精英抑制者，在没有抗病毒治疗的情况下将HIV病毒载量控制在无法检测的水平。所提出的实验研究精英抑制子维持较小水库的能力背后的机制。我们的研究表明，精英抑制因子对治疗耐药的储库细胞具有免疫活性，并可能导致未来的治疗方法，利用免疫反应来减少接受抗病毒治疗的患者的储库大小。