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: 10063845
• 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 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063845
• 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; Cytotoxic T-Lymphocytes; DNA; 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; Population; Positioning Attribute; Production; Proteins; Proviruses; RNA; Race; Recovery; Reporting; Research; Research Personnel; Research Training; Sampling; San Francisco; Shock; Structure; Suggestion; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Therapeutic; Time; Tissue Sample; Training; Translational Research; Viral; Virus Activation; Work; antiretroviral therapy; base; career; clinically relevant; cohort; cytokine; cytokine therapy; cytotoxic; 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; 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.

项目总结/摘要 开始抗逆转录病毒治疗（ART）的HIV阳性个体中，有很大比例的CD 4 + T细胞水平较低， CD 4计数在异常低水平的平台，尽管多年的病毒学抑制的艺术。 这些次优免疫应答者（SoIR）的死亡风险比个体高2-3倍 他们的CD 4计数随着ART适当升高，这种较高的死亡风险持续十年或更长时间。的 SoIR中免疫恢复不佳和死亡率增加的潜在机制仍然很差 定义了一个明显的关联已经出现：SoIR的免疫激活水平明显高于 其他接受ART治疗的人。我们知道通过T细胞受体刺激HIV感染的CD 4细胞， 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，通常的每日抗原刺激的CD 4 s可以产生过度的免疫激活， 携带大量潜伏艾滋病毒的个体。与此一致的是， 感染的CD 4 + T细胞和ART上的低CD 4计数已被多次报道。但是这些研究 没有控制CD 4最低值或ART时间，因此尚不清楚SoIR是否具有更高的感染负担。 CD 4 + T细胞。我们假设，无论是因为HIV潜伏库（LR）的增加， 较大的LR大小或LR诱导的增加与次优免疫应答相关。LR尺寸 和诱导从来没有同时进行评估，但我们将使用有效的新测定方法， 可以区分完整的HIV前病毒和有缺陷的HIV前病毒。我们将确定LR尺寸和电感是否 有助于次优免疫应答，以及设计用于增加CD 4计数的细胞因子疗法是否 也扩大了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 与使用新的完整前病毒DNA检测（IPDA）的次优免疫应答呈正相关， 液滴数字PCR检测，分别定量来自SoIR的样品上的完整和缺陷前病毒 以及从ACTG纵向关联随机试验中确定的年龄和最低点匹配对照 在巴尔的摩、弗朗西斯科和克利夫兰进行了一项研究和三个大型队列研究。对于目标2，我们将确定 使用定量病毒免疫分析，SoIR的感染的CD 4 + T细胞是否更容易从潜伏期诱导 对来自SoIR和匹配对照的血液样品的诱导测定。对于目标3，我们将确定 增加CD 4计数的细胞因子疗法也通过使用IPDA测量HIV LR的大小来扩增HIV LR。 来自外源性IL-7、IL-15和IL-2在治疗的HIV中的临床试验的样品。通过正规的教学培训 以及来自艾滋病毒储存库、艾滋病毒免疫学、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发展独特的技能， 统计学和转化研究。这种培训提供了一个途径，作为一个独立的职业生涯 研究病毒因素对治疗的HIV发病机理的贡献的转化研究者。