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：
8544680
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人群，这也可以导致巨噬细胞 - 热带HIV-1的演变，该巨噬细胞 - 热带HIV-1定义为进入CD4水平较低的细胞的能力。然而，在大脑中感染细胞的分布素和中枢神经系统之外的巨噬细胞 - 循环病毒的发生既有争议，这两个点都是定义消除HIV-1的策略的重要考虑因素。由于最近广泛的认可，我们对病毒种群的理解得到了显着改善，即PCR介导的重组可以争夺系统发育信息，并且在PCR中使用模板终点稀释（单个基因组扩增）对于准确定义病毒群是必不可少的。同样，改进建模进化过程的程序的改进使对系统发育关系的评估更加牢固，例如纳入贝叶斯分析程序野兽。最后，与使用高度可变的单核细胞衍生的巨噬细胞制剂相比，对细胞进入的CD4依赖性的定量描述提供了对巨噬细胞巨型巨型巨型巨星的稳健定义。我们正在应用所有这三个重要的进步，以了解巨噬细胞 - 循环病毒的演变及其在发病机理中的作用，并了解它们创建长寿命的储层的潜力。我们最近将这些工具聚集在一起，以研究病毒隔室化，包括通过检查CSF中的病毒在中枢神经系统中的隔室化。现在，我们已经扩展了这些研究，以包括来自国家神经辅助组织（NNTC）的样本。我们建议利用在尸检前和尸检时采用这些样品的可用性，以绘制受试者中大脑中病毒复制的部位的病毒性和治疗方法。我们还将定义巨噬细胞 - 冰球病毒在大脑中复制中心的填充中心的作用，以及这种进化变体在CNS之外建立的这种类型的变体的能力。最后，我们将研究中断治疗后出现的早期反弹病毒的表型，因为这代表了消除策略必须面对的第一个病毒。