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

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）诱导了病毒抑制和HIV储存库的逐渐衰减， 含有数千至数百万个含有可复制原病毒的潜伏感染的CD 4 + T细胞， 旨在消除HV储库的临床干预试验表明， 在不增强先天性或适应性免疫的情况下触发HIV重新激活， 水库Søgaard博士获得的初步数据表明，引发特定的效应细胞，即， 细胞毒性T淋巴细胞（CTL）和自然杀伤（NK）细胞，增强它们清除感染细胞的能力， 结合输注针对保守病毒蛋白的广泛中和抗体（bNAb）， 通过Fcγ R依赖性机制促进HIV感染细胞的清除。我们和其他人已经证明， 在PLWH中观察到的肠道生态失调调节循环微生物组和代谢组;这些影响 在癌症和HIV感染中输注治疗性Ab后成功的免疫重建。在这个项目中， 已经从45名病毒学抑制受试者的临床试验中获得了样本，这些受试者接受了 先天免疫（TLR 9激动剂）和HIV特异性bNAb。我们将检验一个假设， 免疫将增强HIV特异性适应性免疫应答，并导致顽固状态 新靶细胞的感染。我们提出了三个高度综合和互补的目标。目的 1将确定与病毒载量反弹延迟相关的干预前病毒学特征， 增强免疫控制。在目标2中，我们将确定TLR-9触发的先天免疫抗病毒机制， 通过Ab/Fc受体接合，诱导抗病毒免疫应答，限制病毒传播和促病毒增殖， 通过有效的适应性T和B细胞应答来调节炎症免疫应答。目标3将确定 由微生物组和代谢组预干预触发的先天免疫机制， ATI期间与对照病毒相关的免疫应答。这些目标的实现将依赖于国家的- 现有技术测定病毒学特征（即，整合位点、翻译能力和病毒的完整性 序列），促炎性先天免疫应答的免疫学和表观遗传学特征。这些在 转与适应性免疫反应，控制水平的病毒再活化和时间， 免疫干预后反弹。产生的数据将使我们能够探索先天和适应性的协同作用 有助于病毒学控制和延迟ATI期间病毒反弹的免疫机制。