Functional impact of long non-coding RNA expression on HIV control

 描述(申请人提供)：在艾滋病毒流行的三十年中，很明显，艾滋病毒-1可以通过药物很好地控制，但不能被根除。需要开发针对艾滋病毒感染中重要的宿主因素并提供预防或治愈艾滋病毒-1感染的替代战略。在HIV感染患者中进行的全基因组关联研究已经确定了HIV病毒控制和/或疾病进展的多种宿主基因决定因素。然而，已发现的大多数与疾病相关的SNPs位于非编码区，调节这些关联的功能机制仍不清楚。因此，这些潜在的重要宿主因子不能用作疫苗或药物靶标。在两项不同的GWAS研究中，一个长的基因间非编码RNA(LincRNA)基因的单核苷酸多态(SNP；rs1015164)与HIV病毒控制和向AIDS的进展相关。Rs1015164A等位基因与更高的病毒载量和更快的疾病进展相关，与新的lincRNA CCRL2-5‘AS的高表达水平相关。我们发现lincRNA(CCRL2-5‘AS)增强了HIV辅助受体CCR5的表达。因此，CCRL2-5‘AS的表达变化可能通过增强CCR5的表达和对HIV感染的易感性而有助于HIV病毒的控制。目的1：阐明lincRNA介导的CCR5调控机制，目的2：鉴定和鉴定影响HIV病毒控制的新的lincRNA(S)，目的3：确定lincRNA表达对宿主基因调控和病毒复制的影响。这项拟议的研究将推动新的非编码RNA的发现，以及它们在艾滋病毒发病机制中鲜为人知的作用。这些数据可能导致发现在艾滋病毒病毒控制中重要的尚未被发现的宿主因素，这些宿主因素可能成为未来治疗/疫苗开发的目标。

 DESCRIPTION (provided by applicant): In the three decades of the HIV epidemic, it has become clear that HIV-1 can be well controlled by drugs, but not eliminated. Alternative strategies, which target host factors important in HIV infection and offer protection from or cure of HIV-1 infection, need to be developed. Genome-wide association studies (GWAS) in HIV infected patients have identified a multitude of host genetic determinants of HIV viral control and/or disease progression. However, the majority of the disease-associated SNPs identified are in non-coding regions and the functional mechanisms mediating these associations are still unknown. Therefore, these potentially vital host factors could not be utilized as vaccine or drug targets. A single nucleotide polymorphism (SNP; rs1015164) in close genomic proximity of a long intergenic non-coding RNA (lincRNA) gene associated with HIV viral control and progression to AIDS in two distinct GWAS studies. The rs1015164 A allele, which associated with higher viral loads and more rapid disease progression, correlated with higher expression levels of the novel lincRNA, CCRL2-5'AS. We have found that the lincRNA (CCRL2-5'AS) augments expression of an HIV co-receptor, CCR5. Thus, variation in expression of CCRL2-5'AS may contribute to HIV viral control through enhanced CCR5 expression and greater susceptibility to HIV infection. We propose following specific aims; Aim 1: Elucidate mechanisms of lincRNA mediated CCR5 regulation, Aim 2: Identify and characterize novel lincRNA(s) that influence HIV viral control, Aim 3: Determine the influence of lincRNA expression on host gene regulation and viral replication. The proposed study will fuel discovery of novel non-coding RNAs and their poorly understood role in HIV pathogenesis. These data are likely to result in the finding of yet undiscovered host factors important in HIV viral control that could be targeted for future therapy/vaccine development.