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

描述(申请人提供)：HIV-1不和夫妇中宿主抵抗和控制的mRNA/miRNA调节摘要：尽管保护性或治疗性HIV-1疫苗的开发尚未成功，但许多报告证明，尽管高暴露(暴露于未感染或欧盟)，仍存在对HIV-1感染具有天然抵抗力的个人。此外，大量研究旨在更好地了解那些感染艾滋病毒-1但其宿主反应有效控制艾滋病毒-1复制并将血浆艾滋病毒-1RNA维持在低水平(病毒控制器或VC)的人。许多研究都集中于对EU和VC的先天和后天特征的研究。尽管如此，对HIV-1自然宿主控制的生物学基础仍然知之甚少。我们假设，无论是主要遗传的、获得性的还是兼具两者特征的，宿主对HIV-1感染的抵抗和控制状态都以宿主基因表达的特定模式为特征。由于被称为microRNAs(MiRNAs)的小RNAs越来越多地被发现是控制包括抗病毒防御在内的许多细胞功能的大型基因网络的关键调节因子，我们也提出miRNA的表达模式可能捕捉到宿主对HIV-1的抗性或控制状态的特定特征。然而，研究这一问题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良好特征的HIV-1暴露的个人那里收集RNA。在非洲进行HIV-1预防临床试验和观察性研究的过程中，我们就从HIV-1血清不一致的异性伴侣(一个伴侣感染了HIV-1，另一个没有感染HIV-1)中收集了这样一组样本。这个独特的标本库和相关数据提供了一个难得的机会，可以使用这个独特的流行病学数据库和相关的全血RNA样本来评估宿主对HIV-1的反应的决定因素。具体地说，我们试图评估mRNA和miRNAs在调节宿主对HIV-1的反应中的作用。作为一项探索性的努力，我们建议使用这些独特的现有样本进行初步研究，以确定调节对HIV-1感染的抵抗力或控制的宿主基因表达模式。识别这种宿主途径可以提供重要的洞察力，并有助于开发预防艾滋病毒-1传播或治疗艾滋病毒-1感染的新方法。公共卫生相关性：我们建议使用来自HIV-1血清不一致的异性夫妇(一个伴侣感染HIV-1，另一个未感染HIV-1)样本的独特样本子集来识别调节对HIV-1感染的抵抗力或控制的基因表达模式。对这些途径的识别可以为预防或治疗艾滋病毒-1感染的新方法提供关键的见解。

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.