Perturbing the HIV Reservoir with Immune Stimulation

 描述（由申请人提供）：最近的HIV治疗工作集中在抗逆转录病毒治疗（ART）期间从HIV感染细胞诱导病毒的策略上，从而使细胞库易受宿主免疫系统的攻击，而ART可防止新细胞被感染。不幸的是，这些努力并没有显示出多少活动。另一方面，近20年来已经证明，常规临床疫苗可以诱导感染细胞产生病毒，即使在ART期间也是如此，并且这些诱导水平远高于最近描述的干预措施（例如组蛋白脱乙酰酶抑制剂[HDACi]，IL-7，disulfram）。因此，根据新产生的初步数据，我们提出了一项随机临床试验，以确定两种常用疫苗（抗流感和肺炎球菌）可以刺激免疫系统，并诱导艾滋病毒转录的ART设置。具体来说，我们建议一个随机交叉对照试验，其中56名参与者将接受一次注射，每三个月（流感、肺炎球菌和安慰剂），每次注射后采集多份标本。本研究的主要目的是确定与安慰剂注射相比，受试者接受活性疫苗后细胞相关HIV RNA转录水平的绝对增加是否更高。次要目的是确定这些疫苗是否也：（i）选择性或非选择性地诱导HIV转录（如通过从细胞HIV DNA和RNA群体获得的序列之间的泛混试验所评价的），（ii）影响总HIV DNA水平，（iii）影响复制能力前病毒水平的分数（通过定量病毒生长测定评估），（iv）刺激全身和淋巴细胞免疫活化，和（v）刺激疫苗和HIV特异性免疫应答。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，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.