Elucidating mechanisms of HIV-1 mucosal transmission

阐明 HIV-1 粘膜传播机制

• 批准号: 10428455
• 负责人: JOHN Christopher KAPPES
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10428455
• 关键词: AIDS prevention; AIDS/HIV problem; Address; Affect; Applications Grants; Biology; CD4 Positive T Lymphocytes; Cells; Cervical; Characteristics; Color; Communicable Diseases; Complement; Confocal Microscopy; Data; Dose; Exhibits; Exposure to; Female; Female genitalia; Frequencies; HIV; HIV-1; Heterosexuals; Human; Human Resources; In Situ; Incidence; Individual; Infection; Investigation; Modality; Modeling; Mucous Membrane; Pathway interactions; Pharmaceutical Preparations; Physiological; Population; Predisposition; Prevention; Prevention strategy; Process; Public Health Applications Research; Publishing; Readiness; Recording of previous events; Reporter; Research; Risk; Role; SIV; Services; T-Lymphocyte; Time; Tissues; Tropism; Validation; Veterans; Virus; Virus Replication; Woman; Work; analytical method; innovation; macrophage; men; military service; monocyte; multiparametric imaging; nonhuman primate; pandemic disease; prevent; public health relevance; reproductive tract; spatial relationship; spatiotemporal; therapy development; transmission process; viral transmission; virus host interaction

Project Summary/Abstract HIV/AIDS has spread relentlessly since it was first identified in 1983, causing one of the most devastating pandemics in human history. Historical accounts of infectious diseases show that they can have a major impact on U.S. Armed Forces. With 34 million individuals infected worldwide, HIV-1 poses a significant and persistent threat to force readiness and the stability of many nation-states. The incidence of HIV/AIDS infection among U.S. service personnel is significant and the risk of exposure to HIV-1 by heterosexual intercourse among veterans and service personnel is much greater. Heterosexual HIV-1 transmission from men to women accounts for the majority of new infections worldwide, and notably, women are entering into military service at an increasing rate. The discovery of effective prevention modalities for women is hindered by a lack of basic information about early virus-host interactions in the female genital tract mucosa that underlie the acquisition of HIV-1 infection. Non-human primate (NHP) models of HIV/SIV transmission indicate that macrophages and predominantly CD4 T cells become infected within the first few days after high-dose intravaginal challenge. The observation of early CD4 T cell infection seemed consistent with subsequent published work indicating transmitted/founder (TF) viruses generally exhibit low to moderate tropism for monocyte-derived macrophages (MDM). However, recent published and unpublished data (Preliminary Studies) would argue that this central question regarding HIV-1 transmission biology, and the role of macrophages in particular, warrants additional investigation. Our central hypothesis is that cervical macrophages are required to drive HIV-1 replication and spread in the cervical mucosa. Our corollary hypothesis, though beyond the immediate scope of this application, is that cervical macrophages (cMφs) are required for expansion and spread of HIV-1 infection beyond initial foci of infected CD4 T cell in the mucosa, and thus represent an underlying determinant of mucosal HIV-1 heterosexual transmission in women. To interrogate this central hypothesis, we propose the following specific aims: (1) To characterize the dynamics of HIV-1 infection and replication in human cervical explant tissue; (2) To determine the spatiotemporal relationships between uninfected and HIV-1 infected cMφs and CD4 T lymphocytes in cervical tissue in situ; and (3) To identify cellular determinants of cMφs susceptibility to HIV-1 infection. Our research promise to elucidate critical virus-host interactions that underlie the establishment of HIV-1 infection in the female mucosal genital tract. Validation of our central hypothesis would impart a paradigm shift in the field, and implicate cMφs as a viable early target for the discovery of new HIV/AIDS prevention strategies.

项目概要/摘要 自 1983 年首次发现以来，艾滋病毒/艾滋病一直在无情地传播，造成了最具破坏性的灾难之一 人类历史上的流行病。传染病的历史记载表明，它们可能对人类造成重大影响。 对美国武装部队的影响。全球有 3400 万人感染 HIV-1，它构成了一个重要且 对许多民族国家的战备状态和稳定持续构成威胁。艾滋病毒/艾滋病感染率 美国服役人员中的艾滋病毒感染率很高，异性性交接触 HIV-1 的风险很高 退伍军人和服役人员中的比例要大得多。 HIV-1 从男性到女性的异性传播 全世界新增感染病例占大多数，值得注意的是，女性正在服兵役 不断增加的速度。由于缺乏基本的预防措施，阻碍了对妇女有效预防方式的发现。 有关女性生殖道粘膜中早期病毒与宿主相互作用的信息，这是获得病毒的基础 HIV-1 感染。 HIV/SIV 传播的非人灵长类动物 (NHP) 模型表明，巨噬细胞和 主要是 CD4 T 细胞在高剂量阴道内攻击后的最初几天内被感染。 早期 CD4 T 细胞感染的观察结果似乎与随后发表的研究结果一致，表明 传播/创始 (TF) 病毒通常对单核细胞衍生的巨噬细胞表现出低至中度的趋向性 （主数据管理）。然而，最近发表和未发表的数据（初步研究）认为，这一核心 关于 HIV-1 传播生物学的问题，特别是巨噬细胞的作用，值得补充 调查。我们的中心假设是，宫颈巨噬细胞需要驱动 HIV-1 复制和 扩散到宫颈粘膜。我们的推论假设，尽管超出了本文的直接范围 应用，宫颈巨噬细胞 (cMφs) 是 HIV-1 感染扩展和传播所必需的 超出粘膜中受感染 CD4 T 细胞的初始病灶，因此代表了 女性粘膜 HIV-1 异性传播。为了质疑这个中心假设，我们提出 具体目标如下： (1) 表征人类宫颈中 HIV-1 感染和复制的动态特征 外植体组织； (2) 确定未感染和HIV-1感染cMφ之间的时空关系 和原位宫颈组织中的CD4 T淋巴细胞； (3) 鉴定 cMφs 的细胞决定因素 对 HIV-1 感染的易感性。我们的研究有望阐明潜在的关键病毒与宿主相互作用 HIV-1感染在女性粘膜生殖道中的建立。验证我们的中心假设 将带来该领域的范式转变，并暗示 cMφs 作为发现新材料的可行早期目标 艾滋病毒/艾滋病预防策略。