I2 Control= Modulating Innate Immunity to Achieve Control of HIV

I2 Control= 调节先天免疫以实现对 HIV 的控制

• 批准号: 10731664
• 负责人: Rafick Pierre Sekaly
• 金额: $ 45.37万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-03 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731664
• 关键词: Agonist; B-Lymphocytes; Binding; Biological Assay; CD4 Positive T Lymphocytes; Cells; Clinical; Clinical Trials; Competence; Cytotoxic T-Lymphocytes; Data; Effector Cell; Epigenetic Process; Fc Receptor; HIV; HIV Infections; Immune; Immune response; Immunologics; Infection; Inflammatory; Infusion procedures; Innate Immune Response; Intervention; Intervention Trial; Malignant Neoplasms; Measures; Natural Immunity; Proviruses; Refractory; Sampling; T-Lymphocyte; T-Lymphocyte and Natural Killer Cell; Testing; Therapeutic; Time; Translations; Validation; Viral; Viral Load result; Viral Proteins; adaptive immune response; adaptive immunity; antiretroviral therapy; gut dysbiosis; immune reconstitution; immunological intervention; immunoregulation; innate immune mechanisms; integration site; metabolome; microbiome; multiple omics; neutralizing antibody; response; synergism; viral rebound; Agonist; B-Lymphocytes; Binding; Biological Assay; CD4 Positive T Lymphocytes; Cells; Clinical; Clinical Trials; Competence; Cytotoxic T-Lymphocytes; Data; Effector Cell; Epigenetic Process; Fc Receptor; HIV; HIV Infections; Immune; Immune response; Immunologics; Infection; Inflammatory; Infusion procedures; Innate Immune Response; Intervention; Intervention Trial; Malignant Neoplasms; Measures; Natural Immunity; Proviruses; Refractory; Sampling; T-Lymphocyte; T-Lymphocyte and Natural Killer Cell; Testing; Therapeutic; Time; Translations; Validation; Viral; Viral Load result; Viral Proteins; adaptive immune response; adaptive immunity; antiretroviral therapy; gut dysbiosis; immune reconstitution; immunological intervention; immunoregulation; innate immune mechanisms; integration site; metabolome; microbiome; multiple omics; neutralizing antibody; response; synergism; viral rebound

ABSTRACT - PROJECT 1 Despite antiretroviral treatment (ART) induced viral suppression and gradual decay of the HIV reservoir, PLWH harbor thousands to millions of latently infected CD4+ T cells containing replication competent proviruses, regardless of the duration of ART. Clinical intervention trials aiming to eliminate the HV reservoir have shown that triggering HIV reactivation without boosting innate or adaptive immunity fails to reduce the size of the HIV reservoir. Preliminary data obtained by Dr. Søgaard have shown that priming of specific effector cells, i.e., cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, enhance their ability to eliminate infected cells, combined with the infusion of broadly neutralizing antibodies (bNAbs) against conserved viral proteins will facilitate clearance of HIV infected cells through FcγR-dependent mechanisms. We and others have shown that gut dysbiosis observed in PLWH modulate the circulating microbiome and metabolome; these impact on successful immune reconstitution post infusion of therapeutic Abs in cancer and HIV infection. In this project we have obtained samples from a clinical trial of 45 virologically suppressed subjects treated with an engager of innate immunity (TLR 9 agonist) and HIV specific bNAbs. We will test the hypothesis that targeting innate immunity will enhance the HIV specific adaptive immune response and as well result in a state of refractoriness to the infection of new target cells upon ATI. We propose three highly integrated and complementary aims. Aim 1 will identify virological features pre-intervention that are associated with delays in viral load rebound and enhanced immune control. In Aim 2, we will identify innate immune antiviral mechanisms triggered by TLR-9 and by Ab/Fc receptor engagement that induce an antiviral immune response that limits viral dissemination and pro- inflammatory immune responses through efficacious adaptive T and B cell responses. Aim 3 will identify the innate immune mechanisms triggered by the microbiome and the metabolome pre-intervention that modulate the immune responses associated control viral during the ATI. Execution of these aims will rely on state-of-the- art assays that measure virological features (i.e., integration sites, translation competence and integrity of viral sequences), immunological and epigenetic features of pro-inflammatory innate immune responses. These in turn are associated with adaptive immune responses that control levels of viral reactivation and time to viral rebound post immune intervention. The data generated will enable us to explore synergies of innate and adaptive immune mechanisms that contribute to virological control and the delay of viral rebound during ATI.

摘要 - 项目1 尽管抗逆转录病毒治疗（ART）诱导了HIV储层的病毒抑制和等级衰变，但PLWH 藏有数千至数百万的潜在受感染的CD4+ T细胞，这些CD4+ T细胞含有复制胜任的预科病毒， 不管艺术的持续时间如何。旨在消除HV水库的临床干预试验已显示 触发艾滋病毒重新激活而不促进先天或适应性免疫学不会减少艾滋病毒的大小 水库。 Søgaard博士获得的初步数据表明，特定效应细胞的启动，即 细胞毒性T淋巴细胞（CTL）和天然杀伤（NK）细胞增强了它们消除感染细胞的能力， 结合对保守病毒蛋白的广泛中和抗体（BNAB）的输注 通过FcγR依赖性机制促进艾滋病毒感染细胞的清除。我们和其他人表明 在PLWH中观察到的肠道营养不良调节循环微生物组和代谢组。这些影响 在癌症和艾滋病毒感染中输注治疗性ABS后，成功的免疫重建。在这个项目中，我们 已经从45例用参与者治疗的病毒学抑制受试者的临床试验中获得了样本 先天免疫（TLR 9激动剂）和艾滋病毒特异性BNAB。我们将测试以先天性为目标的假设 免疫将增强HIV特异性适应性免疫响应，并导致难治性 在ATI时感染新靶细胞。我们提出了三个高度融合和互补的目标。目的 1将确定与病毒负荷反弹中延迟有关的病毒学特征 增强的免疫控制。在AIM 2中，我们将确定由TLR-9和 通过AB/FC受体的参与，影响抗病毒免疫激素，该抗病毒免疫响应限制了病毒传播和促进 通过有效的适应性T和B细胞反应产生炎症免疫反应。 AIM 3将确定 由微生物组触发的先天免疫机制和对调节的代谢组预干 免疫反应与ATI期间有关的控制病毒。这些目标的执行将依赖于最新 测量病毒学特征的艺术测定法（即积分位点，转化能力和病毒的完整性 序列），促炎的先天免疫回报的免疫学和表观遗传特征。这些 转弯与控制病毒重新激活水平和病毒时间的自适应免疫复杂有关 免疫干预后反弹。生成的数据将使我们能够探索先天和自适应的协同作用 有助于病毒学控制和ATI病毒反弹延迟的免疫机制。