Defining sex-based differences in the replication-competent myeloid reservoir in virally suppressed people with HIV and SIV-infected ART-suppressed macaques

定义病毒抑制的 HIV 患者和 SIV 感染的 ART 抑制猕猴中复制能力骨髓库的性别差异

基本信息

批准号：
10627964
负责人：
Rebecca Terilli Veenhuis
金额：
$ 71.49万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2021-07-15 至 2026-05-31
项目状态：
未结题

项目摘要

SUMMARY ABSTRACT There is substantial evidence in virologically-suppressed people with HIV (vsPWH) that HIV persists in monocytes and macrophages from blood and tissues. However, despite the likelihood that monocytes and macrophages contribute to the size of the HIV reservoir, and may derail cure-based efforts, limited studies exist investigating whether HIV within monocytes and macrophages can be reactivated to produce functional virus in vsPWH. Additionally, despite known sex-based differences in the CD4 reservoir and immunological response to HIV, there are no reported studies that have assessed sex-based differences in the myeloid (monocyte/macrophage) reservoir in vsPWH. The long-term goal of this proposal is to determine if the myeloid reservoir is a significant concern for cure-based efforts. The overall objectives are to (1) determine if there are sex-based differences in the myeloid reservoir, (2) determine the stability of the myeloid reservoir in the blood (monocyte derived macrophage, MDM) and brain (CNS) of vsPWH and SIV-ART macaques and (3) further develop an easily deployable method to assess the myeloid reservoir in vsPWH. The central hypothesis of this work is that there will be significant differences in the male and female MDM and CNS reactivatable reservoirs in both HIV and SIV, and that these myeloid reservoirs will be stable throughout ART suppression. The rationale for the proposed study is that delineating the size and stability of the MDM and CNS myeloid reservoirs, and potential sex-based differences, will allow for the development of cure-based strategies that appropriately target the myeloid reservoir in men and women with HIV. The central hypothesis will be tested by pursing two specific aims: 1. Define sex-based differences in the MDM HIV reservoir in vsPWH, and 2. Define sex-based differences in the MDM and CNS reservoirs in SIV-ART macaques. These aims will utilize novel HIV or SIV specific techniques, the monocyte derived macrophage quantitative viral outgrowth assay (MDM-QVOA), the CNS macrophage quantitative viral outgrowth assay (CNS-QVOA) and a myeloid adapted intact proviral DNA assay (mIPDA), to measure the replication-competent and intact viral reservoirs in MDM (vsPWH and SIV-ART model) and the CNS (SIV-ART macaques). This research proposal is innovative because it focuses on replication-competence rather than DNA, will elucidate potential sex-based differences and address the stability of myeloid reservoirs in vsPWH and SIV-ART macaques. Finally, this proposal is significant because it will provide essential insights into the monocyte and macrophage reservoir and help to determine if HIV establishes true latency in cells of myeloid origin. Ultimately, such knowledge has the potential to alter cure-based efforts and therapeutics in men and women with HIV as the majority of current efforts are entirely T cell focused.

摘要摘要有大量证据表明，在病毒学受到抑制的 HIV 感染者 (vsPWH) 中，HIV 仍然存在来自血液和组织的单核细胞和巨噬细胞。然而，尽管单核细胞和巨噬细胞会增加艾滋病毒储存库的大小，并可能使基于治疗的努力脱轨，但研究有限目前正在研究单核细胞和巨噬细胞内的 HIV 是否可以被重新激活以产生功能性的 vsPWH 中的病毒。此外，尽管已知 CD4 储存库和免疫学方面存在性别差异对艾滋病毒的反应，目前还没有研究评估骨髓中基于性别的差异 vsPWH 中的（单核细胞/巨噬细胞）储库。该提案的长期目标是确定骨髓是否水库是基于治疗的努力的一个重要关注点。总体目标是 (1) 确定是否存在骨髓库的性别差异，（2）决定血液中骨髓库的稳定性 vsPWH 和 SIV-ART 猕猴的（单核细胞衍生的巨噬细胞，MDM）和大脑（CNS）以及（3）进一步开发一种易于部署的方法来评估 vsPWH 中的骨髓库。这个假设的中心假设研究表明，男性和女性 MDM 和 CNS 可再激活储库存在显着差异在 HIV 和 SIV 中，这些骨髓库在 ART 抑制期间将保持稳定。这拟议研究的基本原理是描述 MDM 和 CNS 骨髓的大小和稳定性储存库和潜在的性别差异将有助于制定基于治疗的策略适当针对男性和女性艾滋病毒携带者的骨髓库。中心假设将被检验追求两个具体目标：1. 明确 vsPWH 中 MDM HIV 储存库的性别差异，2. 定义 SIV-ART 猕猴 MDM 和 CNS 储存库中基于性别的差异。这些目标将利用新型 HIV 或 SIV 特异性技术，单核细胞来源的巨噬细胞定量病毒生长测定（MDM-QVOA）、中枢神经系统巨噬细胞定量病毒生长测定（CNS-QVOA）和骨髓细胞采用完整原病毒 DNA 测定 (mIPDA)，以测量具有复制能力的完整病毒库 MDM（vsPWH 和 SIV-ART 模型）和 CNS（SIV-ART 猕猴）。该研究方案具有创新性因为它关注的是复制能力而不是 DNA，因此将阐明潜在的性别差异并解决 vsPWH 和 SIV-ART 猕猴骨髓库的稳定性问题。最后，这个提案是意义重大，因为它将提供对单核细胞和巨噬细胞库的重要见解，并有助于确定 HIV 是否在骨髓来源的细胞中建立了真正的潜伏期。最终，这些知识有潜力改变针对男性和女性艾滋病毒感染者的基于治愈的努力和疗法，因为目前的大多数努力都是完全以 T 细胞为中心。