HIV-2 latency and its reversal

HIV-2潜伏期及其逆转

基本信息

批准号：
10686343
负责人：
ATHE M. TSIBRIS
金额：
$ 88.67万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686343
关键词：
Acquired Immunodeficiency Syndrome Address Affect Benign Biology CD4 Positive T Lymphocytes Cell Separation Cells Cellular Assay Chromatin Clonal Expansion Complex DNA Data Gene Silencing Genes Genetic Transcription Genome Genomics Goals HIV HIV-1 HIV-2 Heterochromatin Human Infection Knowledge Length Lentivirus Macrophage Measures Modeling Participant Patient Recruitments Patients Peripheral Blood Mononuclear Cell Phylogenetic Analysis Plasma Plasmids Play Primate Lentiviruses Production Proteins Proviruses RNA Reporter Reporting Repression Research Personnel Rest Role Series Techniques Testing Time Transposase Viral Load result Virion Virus Virus Latency antagonist antiretroviral therapy cell type cohort design experimental study gene conservation human DNA in vivo integration site monocyte multimodality permissiveness posttranscriptional recruit single cell analysis single-cell RNA sequencing transcriptome sequencing

项目摘要

Abstract The lentiviruses HIV-1 and HIV-2 cause acquired immunodeficiency syndrome (AIDS) in humans. The conventional wisdom that HIV-2 is a more benign cousin to HIV-1 was recently challenged, however, in a large study that found after 23 years of HIV-2 infection, cumulatively over 90% of participants had AIDS and 80% had died. An effective, safe, and scalable cure for HIV should account for any unique features that may characterize HIV-2 latency. During the course of its replication, HIV-2 integrates into human DNA and creates a reservoir that is a barrier to virus eradication - as is the problem for HIV-1. How similar, or different, these HIV reservoirs may be is unknown. The scientific premise of this proposal is that there are unrecognized unique features of HIV-2 biology that may impact virus eradication efforts, relative to HIV-1. As an example, the HIV-2 Vpx protein has recently been shown to counteract the Human Silencing Hub (HUSH), a highly conserved gene silencing complex known to repress HIV-1 proviruses, in ways that may impact virus latency and the reservoir landscape. HIV-2 vpx reactivates latent provirus transcription in primary human CD4+ T cells through degradation of the HUSH complex. To study HIV-2 latency, we have recruited participants with HIV-2 into our longitudinal HIV Eradication and Latency (HEAL) cohort. Our HIV-2 proviral landscape preliminary data has identified differences between the HIV-1 and HIV-2 proviral landscapes and we see phylogenetic evidence that suggests clonal expansion may maintain the HIV-2 reservoir, findings we propose to explore further in this proposal. We hypothesize that HIV-2 latency reversal differs from HIV-1 reactivation, provide data to support this, and propose experiments to investigate the mechanisms that may explain these observations. The goal of this proposal is to use HIV and host genomic information to define the landscape of HIV-2 integration and investigate the mechanisms that control HIV-2 latency and its reversal. Here we propose to leverage cutting-edge techniques to address important knowledge gaps in our understanding of HIV-2 infection biology. We hypothesize that HIV-2 differs from HIV-1 in integration landscape and reversal from latency and that Vpx plays a key role in these differences. Specific Aims of this proposal are to define the HIV-2 integration landscape in vivo, understand the role of HIV-2 vpx in virus latency, and investigate the transcriptional blocks to HIV-2 latency reversal. Our approaches test hypotheses that are central to understand HIV-2 latency and its reversal.

抽象的 HIV-1和HIV-2的慢病毒导致人类获得的免疫缺陷综合征（AIDS）。这传统的观点，即HIV-2是HIV-1更良性的表亲在HIV-2感染23年后发现的研究，累计超过90％的参与者患有艾滋病，80％的参与者患有死了。艾滋病毒的有效，安全和可扩展的治疗方法应解释任何可能表征的独特功能 HIV-2潜伏期。在复制过程中，HIV-2整合到人DNA中，并创建一个储层消除病毒的障碍 - HIV -1的问题也是如此。这些HIV水库可能是多么相似或不同是未知的。该提议的科学前提是HIV-2的独特特征未被认可相对于HIV-1，可能会影响病毒消除工作的生物学。例如，HIV-2 VPX蛋白具有最近被证明可以抵消人类沉默中心（Hush），这是一种高度保守的基因沉默众所周知，可以以可能影响病毒潜伏期和储层景观的方式来抑制HIV-1病毒。 HIV-2 VPX通过降解来激发原代人CD4+ T细胞中潜在的病毒转录安静的综合体。为了研究HIV-2潜伏期，我们已将HIV-2参与者招募到我们的纵向HIV中和潜伏期（治愈）队列。我们的HIV-2病毒景观初步数据已确定 HIV-1和HIV-2病毒景观，我们看到的系统发育证据表明克隆扩张可能维护HIV-2储层，我们建议在该提案中进一步探索。我们假设HIV-2 潜伏期逆转与HIV-1重新激活不同，提供数据以支持这一点，并提出实验研究可能解释这些观察结果的机制。该建议的目的是使用艾滋病毒和宿主基因组信息来定义HIV-2的景观集成和研究控制HIV-2潜伏期及其逆转的机制。在这里我们建议利用尖端技术来解决我们对HIV-2感染的理解中重要的知识差距生物学。我们假设HIV-2与HIV-1在整合景观和逆转与延迟和逆转方面有所不同 VPX在这些差异中起着关键作用。该提案的具体目的是定义HIV-2整合体内景观，了解HIV-2 VPX在病毒潜伏期中的作用，并研究转录块 HIV-2潜伏期逆转。我们的方法测试假设，这些假设是了解HIV-2潜伏期及其的核心假设逆转。