HIV-1 Persistence in the CNS and Myeloid Cells

HIV-1 在中枢神经系统和骨髓细胞中的持续存在

基本信息

批准号：
8655557
负责人：
Ronald I Swanstrom
金额：
$ 38万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2018-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): It is clear that HIV-1 can establish an independently replicating population in the CNS, and that this can also lead to the evolution of macrophage-tropic HIV-1, defined as the ability to enter cells with low levels of CD4. However, the distributin of infected cells in the brain and the occurrence of macrophage-tropic virus outside of the CNS are both controversial and both of these points are important considerations in defining strategies for the eradication of HIV-1. Our understanding of viral populations has been significantly improved with the recent widespread acknowledgement that PCR-mediated recombination can scramble phylogenetic information, and that the use of template end-point dilution in PCR (single genome amplification) is essential to define viral populations accurately. Similarly, improvements in programs modeling evolutionary processes make the assessment of phylogenetic relationships more robust, for example incorporating the Bayesian analysis program BEAST. Finally, quantitative descriptions of CD4 dependence for cell entry provide a much more robust definition of macrophage tropism than using highly variable monocyte-derived macrophage preparations to try to phenotype viruses that have evolved to use low levels of CD4 to enter cells. We are applying all three of these important advances to understand the evolution of macrophage-tropic viruses and their role in pathogenesis and to understand their potential to create a long-lived reservoir. We have recently brought these tools together to study viral compartmentalization, including compartmentalization in the CNS by examining virus in the CSF. We have now extended these studies to include samples from the National NeuroAIDS Tissue Consortium (NNTC). We propose to exploit the availability of these samples, taken both prior to and at autopsy, to map the sites of viral replication in the brain in subjects how are viremic and those on therapy. We will also define the role of macrophage-tropic virus in populating centers of replication in the brain, and the ability of this type of evolutionary variant to become established outside of the CNS. Finally, we will examine the phenotype of the early rebound virus that appears after therapy discontinuation, as this represents the first virus that eradication strategies must confront.

描述（由申请人提供）：很明显，HIV-1 可以在中枢神经系统中建立独立复制的群体，并且这也可以导致嗜巨噬细胞的 HIV-1 的进化，定义为进入具有低水平细胞的能力。 CD4 水平。然而，受感染细胞在大脑中的分布以及嗜巨噬细胞病毒在中枢神经系统外的出现都存在争议，这两点都是制定根除 HIV-1 策略时需要考虑的重要因素。最近人们普遍认识到 PCR 介导的重组可以扰乱系统发育信息，并且在 PCR（单基因组扩增）中使用模板终点稀释对于准确定义病毒种群至关重要，因此我们对病毒种群的了解已得到显着改善。同样，进化过程建模程序的改进使得系统发育关系的评估更加稳健，例如结合贝叶斯分析程序 BEAST。最后，与使用高度可变的单核细胞来源的巨噬细胞制剂来尝试对已进化为使用低水平的 CD4 进入细胞的病毒进行表型分析相比，对细胞进入的 CD4 依赖性的定量描述为巨噬细胞向性提供了更可靠的定义。我们正在应用所有这三项重要进展来了解嗜巨噬细胞病毒的进化及其在发病机制中的作用，并了解它们创造长寿病毒库的潜力。我们最近将这些工具结合在一起来研究病毒区室化，包括通过检查脑脊液中的病毒来研究中枢神经系统的区室化。我们现在将这些研究扩展到包括来自国家神经艾滋病组织联盟 (NNTC) 的样本。我们建议利用尸检前和尸检时采集的这些样本的可用性，来绘制病毒血症患者和接受治疗的受试者大脑中病毒复制的位点。我们还将定义嗜巨噬细胞病毒在大脑复制中心中的作用，以及这种类型的进化变异在中枢神经系统之外建立的能力。最后，我们将检查治疗停止后出现的早期反弹病毒的表型，因为这是根除策略必须面对的第一种病毒。