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

摘要：尽管保护性或治疗性HIV-1疫苗的开发尚未成功，但许多报告已经证明，尽管暴露于高暴露（暴露于未感染或EU），但存在对HIV-1感染具有天然抗性的个体。此外，大量的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复制并维持低水平血浆HIV-1 RNA（病毒控制器或VC）的个体。许多研究都集中在EU和VC的先天和后天特征上。尽管如此，自然宿主控制HIV-1的生物学基础仍然知之甚少。我们假设，宿主对HIV-1感染的抵抗和控制状态，无论是主要是遗传的、获得的，还是兼而有之，都是以宿主基因表达的特定模式为特征的。由于越来越多的被称为microRNAs （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抵抗或控制HIV-1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从具有明确特征的HIV-1暴露的个体中收集RNA。在非洲进行HIV-1预防临床试验和观察性研究的过程中，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为利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反应的决定因素提供了难得的机会。具体来说，我们试图评估mRNA和mirna在调节宿主对HIV-1的反应中的作用。作为一项探索性工作，我们建议使用这些独特的现有标本进行初步研究，以确定调节HIV-1感染抗性或控制的宿主基因表达模式。识别这些宿主途径可以提供重要的见解，并有助于开发预防HIV-1传播或治疗HIV-1感染的新方法。公共卫生相关性：我们建议使用来自HIV-1血清不一致异性恋夫妇（一方感染HIV-1，另一方未感染HIV-1）的独特样本子集来鉴定调节HIV-1感染抵抗或控制的基因表达模式。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.