Perturbing the HIV Reservoir with Immune Stimulation

通过免疫刺激扰乱 HIV 储存库

基本信息

批准号：
9212094
负责人：
David Mitchell Smith
金额：
$ 76.65万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9212094
关键词：
Antigens Biological Assay Blood Cells CD4 Positive T Lymphocytes Cells Clinical Controlled Clinical Trials DNA Data Future Genetic Transcription Genital system Goals HIV HIV therapy Herpesviridae Histone Deacetylase Inhibitor Human Immune response Immune system Immunization Individual Inflammatory Influenza Influenza vaccination Injection of therapeutic agent Interleukin-7 Intervention Lymphocyte Measurable Measures Participant Placebo Control Placebos Plasma Pneumococcal vaccine Population Production Proviruses Published Comment RNA Randomized Randomized Clinical Trials Review Literature Sampling Source Streptococcus pneumoniae T-Cell Activation Testing Time Vaccination Vaccines Viral Vorinostat antiretroviral therapy base control trial cytokine design double-blind placebo controlled trial immune activation influenza virus vaccine killings microbial prevent public health relevance response sample collection virology

项目摘要

DESCRIPTION (provided by applicant): Most recent HIV cure efforts have focused on strategies to induce virus from HIV-infected cells during antiretroviral therapy (ART), thus leaving the cellular reservoir vulnerable to the host immune system, while ART prevents new cells from being infected. Unfortunately, such efforts have not demonstrated much activity. On the other hand, it has been documented for almost two decades that routine clinical vaccines can induce viral production from infected cells, even during ART, and that these levels of induction are much higher than those seen by recently described interventions (e.g. histone deacetylase inhibitors [HDACi], IL-7, disulfram). Therefore, based on newly generated preliminary data, we propose a randomized clinical trial to determine how two commonly used vaccines (against Influenza and Pneumococcus) can stimulate the immune system and induce HIV transcription in the setting of ART. Specifically, we propose a randomized cross-over controlled trial where 56 participants will receive one injection every three months (Influenza, Pneumococcal, and Placebo) in random order with multiple specimen collections after each injection. The primary objective of this study will be to determine if participants have a higher absolute increase in levels of cell-associated HIV RNA transcription after receiving active vaccines when compared placebo injection. Secondary objectives will be to determine if these vaccines also: (i) induce HIV transcription selectively or non-selectively (as evaluated by panmixis tests between sequences obtained from cellular HIV DNA and RNA populations), (ii) influence total HIV DNA levels, (iii) influence fraction of replication competent proviral levels (s evaluated by quantitative viral outgrowth assays), (iv) stimulate generalized and lymphocyte immune activation, and (v) stimulate vaccine- and HIV- specific immune responses. To best delineate these possible effects, we will also measure other sources of incidental immune stimulation, like shedding of herpesviruses, microbial translocation and incident illnesses.

描述（由适用提供）：最新的HIV治疗努力集中在抗逆转录病毒疗法（ART）期间诱导感染HIV感染细胞病毒的策略，因此使细胞疗养者容易受到宿主免疫系统的影响，而ART则防止新细胞被感染。不幸的是，这样的努力并没有表现出太多的活动。另一方面，已经记录了近二十年的记录，即使在ART期间，常规临床疫苗也可以诱导感染细胞的病毒产生，并且这些诱导水平远高于最近描述的干预措施（例如组蛋白脱乙酰基酶抑制剂[HDACI]，IL-7，IL-7，IL-7，DISULFRAM）。因此，基于新生成的初步数据，我们提出了一项随机临床试验，以确定两种常用的疫苗（反对流感和肺炎球菌）如何刺激免疫学系统并在艺术环境中诱导HIV转录。具体而言，我们提出了一项随机交叉对照试验，其中56名参与者每三个月将每三个月收到一次注射（流感，肺炎球菌和安慰剂和安慰剂），每次注射后都有多个样本收集。这项研究的主要目的是确定参与者在比较安慰剂注射后接受活性疫苗后，与细胞相关的HIV RNA转录水平的绝对水平更高。 Secondary objects will be to determine if these vaccines also: (i) Induce HIV transcription selectively or non-selectively (as evaluated by panmixis tests between sequences obtained from cellular HIV DNA and RNA populations), (ii) influence total HIV DNA levels, (iii) influence fraction of replication competent proviral levels (s evaluated by quantitative viral outgrowth assays), (iv) stimulate generalized and淋巴细胞免疫激活，（v）刺激疫苗和特异性免疫复杂。为了最好地描述这些可能的影响，我们还将测量其他偶然免疫刺激的来源，例如疱疹病毒的脱落，微生物易位和事件疾病。