The HIV Latent Reservoir, Suboptimal Immune Response on Antiretroviral Therapy, and Exogenous Cytokine Therapies

HIV 潜伏库、抗逆转录病毒治疗的次优免疫反应和外源细胞因子治疗

• 批准号: 10531134
• 负责人: Annukka Aida Rose Antar
• 金额: $ 19.87万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10531134
• 关键词: AIDS clinical trial group; Age; Baltimore; Biological Assay; Biological Markers; Biometry; Blood; Blood specimen; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; Cell Count; Cells; Cessation of life; Characteristics; Clinical; Clinical Research; Clinical Trials; Cohort Studies; Collaborations; Cytotoxic T-Lymphocytes; DNA; Dedications; Fellowship; Frequencies; HIV; HIV Seropositivity; IL7 gene; Immune; Immune response; Immunologic Techniques; Immunology; Immunotherapy; Individual; Interleukin-15; Interleukin-2; Knowledge; Lead; Link; Lymphoid Tissue; Measurement; Measures; Mentors; Mentorship; Methods; Morbidity - disease rate; Outcome; Participant; Pathogenesis; Pathway interactions; Persons; Population; Positioning Attribute; Production; Proliferating; Proteins; Proviruses; RNA; Race; Recovery; Reporting; Research Personnel; Research Training; Sampling; San Francisco; Shock; Structure; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Therapeutic; Time; Tissue Sample; Training; Translational Research; Viral; Virus Activation; Work; antiretroviral therapy; career; clinically relevant; cohort; cytokine; cytokine therapy; design; digital; high risk; high risk population; immune activation; in vivo; indexing; insight; latent HIV reservoir; mortality; mortality risk; randomized trial; reactivation from latency; sex; skills; statistics; therapeutic development; therapeutic vaccine; therapy design; translational scientist; virology

Project Summary/Abstract A significant percentage of HIV-positive individuals who start antiretroviral therapy (ART) with a low CD4+ T cell count have CD4 counts that plateau at abnormally low levels despite years of virologic suppression on ART. The risk of death for these suboptimal immune responders (SoIRs) is 2-3 times higher than that of individuals whose CD4 count rises appropriately with ART, and this higher risk of death persists for a decade or more. The mechanisms underlying the suboptimal immune recovery and increased mortality rates in SoIRs remain poorly defined. One clear association has emerged: SoIRs have significantly higher levels of immune activation than other ART-treated individuals. We know that stimulation of HIV-infected CD4s through the T cell receptor results in HIV RNA and protein production and recognition by HIV-specific cytotoxic T lymphocytes. This suggests that the usual daily antigenic stimulation of CD4s could produce excess immune activation in individuals with a very large burden of latent HIV. Concordantly, a correlation between the frequency of infected CD4+ T cells and low CD4 counts on ART has been reported several times. However, these studies did not control for CD4 nadir or time on ART, so it is not clear whether SoIRs have a higher burden of infected CD4+ T cells. We hypothesize that increased induction from the HIV latent reservoir (LR), whether because of a larger LR size or increased inducibility from the LR, is correlated with suboptimal immune response. LR size and inducibility have never been simultaneously evaluated, but we will do so using efficient new assays that can discriminate intact from defective HIV proviruses. We will determine whether LR size and inducibility contribute to suboptimal immune response and whether cytokine therapies designed to increase CD4 counts also expand the LR. For Aim 1, we will determine whether the size of the HIV LR in blood and lymphoid tissue is positively correlated with suboptimal immune response using the new intact proviral DNA assay (IPDA), a droplet digital PCR assay that separately quantifies intact and defective proviruses, on samples from SoIRs and age- and nadir-matched controls identified from within the ACTG Longitudinal Linked Randomized Trials study and three large cohorts in Baltimore, San Francisco, and Cleveland. For Aim 2, we will determine whether infected CD4+ T cells of SoIRs are more readily inducible from latency using a quantitative viral induction assay on blood samples from SoIRs and matched controls. For Aim 3, we will determine whether cytokine therapies that increase CD4 count also expand the HIV LR by using the IPDA to measure LR size in samples from clinical trials of exogenous IL-7, IL-15, and IL-2 in treated HIV. Through formal didactic training and structured mentorship from experts in HIV reservoirs, HIV immunology, clinical research, and biostatistics, the PI will develop a unique skillset in HIV latency techniques, immunological techniques and knowledge, statistics, and translational research. This training provides a pathway to an independent career as a translational investigator researching the contribution of viral factors to the pathogenesis of treated HIV.

项目概要/摘要 相当大比例的 HIV 阳性个体在 CD4+ T 细胞水平较低的情况下开始抗逆转录病毒治疗 (ART) 尽管经过多年的 ART 病毒学抑制，CD4 计数仍维持在异常低水平。 这些次优免疫反应者 (SoIR) 的死亡风险比个体高 2-3 倍 接受 ART 治疗后，其 CD4 计数会适当上升，并且这种较高的死亡风险会持续十年或更长时间。这 SoIR 中免疫恢复欠佳和死亡率增加的潜在机制仍然很差 定义的。一个明显的关联已经出现：SoIR 的免疫激活水平明显高于 SoIR。 其他接受 ART 治疗的个体。我们知道，通过 T 细胞受体刺激 HIV 感染的 CD4 导致 HIV RNA 和蛋白质的产生以及 HIV 特异性细胞毒性 T 淋巴细胞的识别。这 表明通常每日对 CD4 进行抗原刺激可能会在体内产生过度的免疫激活 潜伏艾滋病毒负担非常大的人。相应地，频率之间存在相关性 CD4+ T 细胞感染和 ART 治疗中 CD4 计数低的情况已多次被报道。然而，这些研究 没有控制 CD4 最低点或 ART 时间，因此尚不清楚 SoIR 是否具有更高的感染负担 CD4+ T 细胞。我们假设 HIV 潜伏病毒库 (LR) 的诱导增加，是否是因为 较大的 LR 大小或 LR 的诱导能力增加与次优免疫反应相关。 LR尺寸 和诱导性从未被同时评估，但我们将使用有效的新测定法来做到这一点 可以区分完整的和有缺陷的HIV原病毒。我们将确定 LR 大小和诱导能力是否 导致免疫反应不理想以及细胞因子疗法是否旨在增加 CD4 计数 还扩大了LR。对于目标 1，我们将确定血液和淋巴组织中 HIV LR 的大小是否 使用新的完整原病毒 DNA 测定 (IPDA) 与次优免疫反应呈正相关， 液滴数字 PCR 检测可对 SoIR 样品中的完整和缺陷原病毒进行单独定量 以及从 ACTG 纵向连锁随机试验中确定的年龄和最低匹配对照 研究以及巴尔的摩、旧金山和克利夫兰的三个大型队列。对于目标 2，我们将确定 使用定量病毒分析，SoIR 的受感染 CD4+ T 细胞是否更容易从潜伏期诱导出来 对 SoIR 和匹配对照的血样进行诱导测定。对于目标 3，我们将确定是否 增加 CD4 计数的细胞因子疗法还通过使用 IPDA 测量 LR 大小来扩大 HIV LR 来自治疗 HIV 的外源性 IL-7、IL-15 和 IL-2 临床试验的样本。通过正规的教学培训 以及 HIV 储存库、HIV 免疫学、临床研究和生物统计学专家的结构化指导， PI 将在 HIV 潜伏技术、免疫学技术和知识方面开发一套独特的技能， 统计和转化研究。该培训为作为独立职业者提供了一条途径 研究病毒因素对治疗艾滋病毒发病机制的贡献的转化研究者。

项目成果

Clustering of SARS-CoV-2 Infections in Households of Patients Diagnosed in the Outpatient Setting in Baltimore, Maryland.

• DOI: 10.1093/ofid/ofab121
• 发表时间: 2021-04
• 期刊: Open forum infectious diseases
• 影响因子: 4.2
• 作者: Demko ZO;Antar AAR;Blair PW;Lambrou AS;Yu T;Brown D;Walch SN;Armstrong DT;Mostafa HH;Keruly JC;Thomas DL;Manabe YC;Mehta SH;Ambulatory COVID Study Team
• 通讯作者: Ambulatory COVID Study Team

Remdesivir for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials.

• DOI: 10.1016/j.cct.2021.106272
• 发表时间: 2021-03
• 期刊: Contemporary clinical trials
• 影响因子: 2.2
• 作者: Al-Abdouh A;Bizanti A;Barbarawi M;Jabri A;Kumar A;Fashanu OE;Khan SU;Zhao D;Antar AAR;Michos ED
• 通讯作者: Michos ED