mRNA/miRNA Regulation of Host Resistance and Control in HIV-1 Discordant Couples

描述（由申请人提供）：mRNA/miRNA调节宿主抗性和HIV-1不一致夫妇的控制摘要：虽然保护性或治疗性HIV-1疫苗的开发尚未成功，但许多报告已记录了尽管高暴露（暴露未感染或EU），但仍存在对HIV-1感染具有天然抗性的个体。此外，大量研究旨在更好地了解感染HIV-1但其宿主反应有效控制HIV-1复制并将血浆HIV-1 RNA维持在低水平（病毒控制者或VC）的个体。许多研究都集中在表征欧盟和VC的先天和后天特征。尽管如此，对自然宿主控制HIV-1的生物学基础仍然知之甚少。我们假设，无论是主要遗传，获得或两者的功能，宿主的抵抗和控制HIV-1感染的状态的特点是由特定的宿主基因表达模式。由于越来越多的被称为microRNA（miRNAs）的小RNA已被确定为控制许多细胞功能（包括抗病毒防御）的大型基因网络的关键调节因子，我们还提出，miRNA表达模式可能捕获宿主对HIV-1的抗性或控制状态的特定特征。然而，研究这一点所需的标本很难获得，因为它们需要前瞻性的随访和RNA收集的个人具有良好的特征的HIV-1暴露。在非洲进行HIV-1预防临床试验和一项观察性研究期间，我们从HIV-1血清不一致的异性恋夫妇（一方感染HIV-1，另一方未感染HIV-1）中收集了这样一组标本。这种独特的标本库和相关数据提供了一个难得的机会，使用这种独特的流行病学数据库和相关的全血RNA标本来评估宿主对HIV-1反应的决定因素。具体而言，我们试图评估mRNA和miRNA在调节宿主对HIV-1的反应中的作用。作为一种探索性的努力，我们建议使用这些独特的现有标本进行试点研究，以确定宿主基因的表达模式调节抵抗或控制HIV-1感染。识别这些宿主途径可以提供关键的见解，并有助于开发新的方法来预防HIV-1传播或治疗HIV-1感染。公共卫生相关性：我们建议使用一个独特的标本子集的样本从HIV-1血清不一致的异性恋夫妇（与一个合作伙伴HIV-1感染和其他HIV-1未感染），以确定基因表达模式，调节抵抗或控制HIV-1感染。识别这些途径可以为预防或治疗HIV-1感染的新方法提供重要的见解。

DESCRIPTION (provided by applicant): mRNA/miRNA Regulation of Host Resistance and Control in HIV-1 Discordant Couples Abstract: Although development of a protective or therapeutic HIV-1 vaccine has not yet been successful, numerous reports have documented the existence of individuals who have natural resistance to HIV-1 infection despite high exposure (exposed uninfected or EU). Furthermore, a great deal of study has been directed at better understanding individuals who become HIV-1 infected but whose host response effectively controls HIV-1 replication and maintain plasma HIV-1 RNA at low levels (viral controllers or VC). Many studies have focused on characterizing both innate and acquired characteristics of EU and VC. Despite this, the biological basis for natural host control of HIV-1 is still poorly understood. We hypothesize that, whether primarily inherited, acquired or with features of both, states of host resistance to and control of HIV-1 infection are characterized by specific patterns of host gene expression. Since, increasingly, small RNAs called microRNAs (miRNAs) have been identified as key regulators of large networks of genes controlling many cellular functions including antiviral defense, we also propose that patterns of miRNA expression may capture specific characteristics of the host state of resistance to or control of HIV-1. However, the specimens needed to study this are difficult to obtain, since they require prospective follow-up and RNA collection from individuals with well-characterized HIV-1 exposure. During the course of conducting HIV-1 prevention clinical trials and an observational study in Africa, we have collected just such a set of specimens from HIV-1 serodiscordant heterosexual couples (one partner HIV-1 infected and the other HIV-1 uninfected). This unique specimen repository and associated data provide a rare opportunity to use this unique epidemiological database and associated whole blood RNA specimens to assess determinants of host response to HIV-1. Specifically we seek to evaluate the role of mRNA and miRNAs in regulating host response to HIV-1. As an exploratory effort, we propose to use these unique existing specimens for pilot studies to identify host gene expression patterns regulating resistance to or control of HIV-1 infection. Identification of such host pathways could provide critical insights and help develop novel approaches to prevent HIV-1 transmission or to treat HIV-1 infection. PUBLIC HEALTH RELEVANCE: We propose to use a unique specimen subset of samples from HIV-1 serodiscordant heterosexual couples (with one partner HIV-1 infected and the other HIV-1 uninfected) to identify gene expression patterns that regulate resistance to or control of HIV-1 infection. Identification of such pathways could provide critical insights toward new approaches to prevention or treatment of HIV-1 infection.