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)导致了病毒抑制和HIV储存库的逐渐腐烂，但PLWH 窝藏数千至数百万潜伏感染的含有复制能力前病毒的CD4+T细胞， 不管艺术的持续时间有多长。旨在消除HV储存库的临床干预试验表明 在没有增强先天免疫或获得性免疫的情况下触发艾滋病毒重新激活未能减少艾滋病毒的大小 水库。S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)和自然杀伤(NK)细胞，增强其清除感染细胞的能力， 结合注射针对保守病毒蛋白的广谱中和抗体(BNAbs)将 通过FcγR依赖机制促进艾滋病毒感染细胞的清除。我们和其他人已经证明了 在PLWH中观察到的肠道菌群失调调节循环微生物组和代谢组；这些影响 注射治疗性抗体治疗癌症和HIV感染后成功的免疫重建。在这个项目中，我们 已经从45名病毒学抑制的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(TLR9激动剂)和HIV特异性bNAbs。我们将验证这样的假设，即目标是天生的 免疫会增强HIV特异性适应性免疫反应，也会导致难以控制的状态 新靶细胞对ATI的感染作用。我们提出了三个高度整合和相辅相成的目标。目标 1将确定干预前与病毒载量反弹延迟相关的病毒学特征和 增强免疫控制。在目标2中，我们将确定TLR-9和TLR-9触发的天然免疫抗病毒机制。 通过抗体/Fc受体的结合，诱导抗病毒免疫反应，限制病毒的传播和促进 通过有效的适应性T和B细胞反应的炎性免疫反应。目标3将确定 微生物组和代谢组预干预所触发的先天免疫机制 在ATI期间，相关的免疫反应控制病毒。这些目标的实现将取决于最新情况- 测量病毒学特征(即整合位点、翻译能力和病毒完整性)的ART分析 致炎先天免疫反应的免疫学和表观遗传学特征。这些输入 TURN与控制病毒重新激活水平和病毒存活时间的获得性免疫反应有关 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效应 在ATI期间有助于病毒学控制和延缓病毒反弹的免疫机制。