HIV-2 latency and its reversal

HIV-2潜伏期及其逆转

• 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
• 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

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.

摘要 慢病毒HIV-1和HIV-2导致人类获得性免疫缺陷综合征（AIDS）。的 然而，HIV-2是HIV-1的一个更良性的表亲的传统观点最近受到了挑战，在很大程度上， 一项研究发现，在感染HIV-2 23年后，累积超过90%的参与者患有艾滋病，80%的参与者患有艾滋病。 死了一个有效的，安全的，可扩展的艾滋病毒治疗应该考虑到任何独特的特征， HIV-2潜伏期。 在其复制过程中，HIV-2整合到人类DNA中，并创造了一个储存库， 这是根除病毒的障碍，就像HIV-1的问题一样。这些HIV宿主有多相似或不同 不明这一提议的科学前提是，HIV-2存在未被认识到的独特特征 生物学可能会影响病毒根除工作，相对于HIV-1。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），一种高度保守的基因沉默 已知抑制HIV-1前病毒的复合物，其方式可能会影响病毒潜伏期和宿主景观。 HIV-2 vpx通过降解原代人CD 4 + T细胞中的前病毒， HUSH复合体。 为了研究HIV-2的潜伏期，我们招募了HIV-2参与者， 和延迟（HEAL）队列。我们的HIV-2前病毒景观初步数据已经确定了 HIV-1和HIV-2的前病毒景观，我们看到系统发育的证据表明，克隆扩张可能 维持HIV-2水库，我们建议在本提案中进一步探讨研究结果。我们假设HIV-2 潜伏期逆转不同于HIV-1再激活，提供数据支持这一点，并提出实验， 调查可能解释这些观察结果的机制。 该提案的目标是利用HIV和宿主基因组信息来定义HIV-2的景观 整合和研究控制HIV-2潜伏期及其逆转的机制。在此，我们建议 利用尖端技术来填补我们对HIV-2感染的认识方面的重要知识空白 生物学我们假设HIV-2与HIV-1在整合景观和潜伏期逆转方面不同， Vpx在这些差异中起着关键作用。该提案的具体目标是确定HIV-2整合 体内景观，了解HIV-2 vpx在病毒潜伏期中的作用，并研究转录阻滞， HIV-2潜伏期逆转。我们的方法测试了对理解HIV-2潜伏期及其 逆转