HIV-2 latency and its reversal

HIV-2潜伏期及其逆转

• 批准号: 10832159
• 负责人: ATHE M. TSIBRIS
• 金额: $ 22.23万
• 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/10832159
• 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; Funding; 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; Sampling; 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. This supplement requests funds to cover an unanticipated lack of access to a single cell sequencer for HIV-infected samples.

摘要 慢病毒HIV-1和HIV-2会导致人类获得性免疫缺陷综合症(AIDS)。这个 然而，认为HIV-2是HIV-1的更良性表亲的传统观点最近在很大程度上受到了挑战 研究发现，在感染HIV-2 23年后，累计超过90%的参与者患有艾滋病，80%的参与者患有 死了。一种有效、安全和可扩展的艾滋病毒治疗方法应该考虑到可能具有以下特征的任何独特特征 HIV-2潜伏期。 在其复制过程中，HIV-2整合到人类DNA中，并创建了一个储存库 消除病毒的障碍--艾滋病毒-1的问题也是如此。这些艾滋病毒宿主可能有多相似，或有多不同 是未知的。这项提议的科学前提是，艾滋病毒-2有一些未被认识到的独特特征 相对于HIV-1，可能影响病毒根除努力的生物学。例如，HIV-2 VPX蛋白具有 最近被证明可以对抗人类沉默中心(HUSH)，这是一种高度保守的基因沉默 已知可抑制HIV-1前病毒的复合体，其方式可能会影响病毒潜伏期和水库景观。 HIV-2 VPX通过降解原代人类CD4+T细胞重新激活潜伏的前病毒转录 安静的情结。 为了研究HIV-2潜伏期，我们招募了HIV-2携带者参加我们的纵向根除HIV 和潜伏期(治愈)队列。我们的HIV-2前病毒情况初步数据确定了 HIV-1和HIV-2前病毒景观和我们看到的系统发育证据表明克隆扩张可能 保持HIV-2的储存库，这是我们建议在本提案中进一步探索的发现。我们假设HIV-2病毒 潜伏期逆转不同于HIV-1重新激活，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。 这项提案的目标是使用艾滋病毒和宿主基因组信息来定义艾滋病毒-2的图景 整合并研究控制HIV-2潜伏期及其逆转的机制。在此，我们建议 利用尖端技术解决我们在了解艾滋病毒-2感染方面的重要知识差距 生物学。我们假设HIV-2与HIV-1在整合格局和潜伏期和逆转方面不同 VPX在这些差异中起着关键作用。这项提案的具体目标是定义HIV-2整合 了解HIV-2 VPX在病毒潜伏时间中的作用，并研究转录阻断 HIV-2潜伏期逆转。我们的方法测试了对理解HIV-2潜伏期和其 反转。本补编要求提供资金，以弥补无法获得单个细胞测序仪的意外情况 感染艾滋病毒的样本。