Perturbing the HIV Reservoir with Immune Stimulation

 描述(申请人提供)：大多数最近的艾滋病毒治疗努力都集中在抗逆转录病毒疗法(ART)期间从艾滋病毒感染细胞中诱导病毒的策略，从而使细胞储备库容易受到宿主免疫系统的攻击，而ART则防止新的细胞被感染。不幸的是，这些努力并没有显示出太多的活动。另一方面，近20年来，已有文献证明，常规临床疫苗可以诱导感染细胞产生病毒，即使在抗逆转录病毒治疗期间也是如此，而且这些诱导水平远远高于最近描述的干预措施(例如组蛋白去乙酰化酶抑制剂[HDACi]、IL-7、二硫氰胺)。因此，基于新产生的初步数据，我们建议进行一项随机临床试验，以确定两种常用疫苗(针对流感和肺炎球菌)如何在抗逆转录病毒治疗的背景下刺激免疫系统并诱导HIV转录。具体地说，我们提出了一项随机交叉对照试验，其中56名参与者将每三个月接受一次注射(流感、肺炎球菌和安慰剂)，每次注射后进行多次样本采集。这项研究的主要目标将是确定与安慰剂注射相比，参与者在接种活性疫苗后是否有更高的细胞相关艾滋病毒RNA转录水平的绝对增加。次要目标是确定这些疫苗是否还：(I)选择性或非选择性地诱导艾滋病毒转录(通过从细胞艾滋病毒DNA和RNA群体获得的序列之间的PanMiis测试进行评估)，(Ii)影响艾滋病毒总DNA水平，(Iii)影响具有复制能力的前病毒水平(通过定量病毒生长试验评估S)，(Iv)刺激全身性和淋巴细胞免疫激活，以及(V)刺激疫苗和艾滋病毒特异性免疫反应。为了更好地描述这些可能的影响，我们还将测量其他附带免疫刺激来源，如疱疹病毒的脱落、微生物易位和偶发疾病。

 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.