Investigating the distribution & impact of HIV-specific broadly neutralising antibodies on mucosal immunity and the HIV reservoir in rectal tissue

调查分布

• 批准号: MR/W024454/1
• 负责人: Ming Jie Lee
• 金额: $ 38.38万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW024454%2F1
• 关键词: Investigating; distribution; impact; HIV; specific

Antiretroviral treatment (ART) has improved survival for people with HIV. But it cannot cure HIV as ART cannot remove HIV from cells containing virus in a resting state, known as the HIV reservoir. Current ART options usually requires daily oral medications, challenges include long-term side effects, treatment fatigue, drug resistance and expense. Broadly neutralising antibodies (bNAbs) are a new type of HIV treatment that may provide a safe, effective, and long-acting alternative to ART.Early studies suggest bNAbs may 'train' the immune system leading to long lasting HIV-specific responses. Monkeys given bNAbs early in SHIV infection, demonstrated virus control for up to 4 years. Two individuals treated with bNAbs in a small human study have unexpectedly continued to maintain undetectable virus levels in blood even beyond 30 weeks. However these studies were not randomised.The largest reservoir of HIV in the body is in the gut. It can be up to 5 times larger than in blood. It is uncertain if bNAbs enter gut tissue as well as in blood. Immune responses in the gut also differ from blood in many ways, such as slower recovery even after starting ART. Finally, we do not know how bNAbs affect the gut HIV reservoir.The RIO trial is an ongoing funded study. It compares a single dose of two types of bNAbs against inactive drug (placebo). Participants then stop ART and will return for frequent viral load tests. When the virus is detectable in blood, they will restart ART. Participants receiving placebo will be given the bNAbs after restarting ART. The RIO trial provides a unique chance to study the impact of bNAbs on the gut immune system and HIV reservoir through rectal biopsies.I will study rectal biopsies samples collected from RIO participants before and after they receive the study drugs (see Annex 1). These small 3mm biopsies are collected by an experienced clinician through a safe and painless procedure in clinic, using a short plastic tube in their rectum. This is less invasive than other common gut procedures such as colonoscopies and have minimal risks.The project aims to answer 3 research questions:1: Are the bNAbs levels in the gut comparable to blood?Paired rectal tissue and blood bNAb levels will be measured using a highly sensitive test that can measure even single molecules of bNAbs present. If peak gut tissue bNAb concentrations are comparable to blood, these data will support further research of bNAbs for the eradication of HIV gut reservoir. This work will be done on an expected n = 10 participants who are randomised to receive the bNAbs in the main study. 2: Do bNAbs 'train' immune cells in the gut?I will use fluorescent antibody 'dyes' to look for the presence of both bNAbs and immune cells in biopsy sections through an automatic microscope. If bNAbs can 'train' HIV-specific immune responses, we will expect to see bNAbs in areas of immune cells called germinal centres. Learning how bNAbs 'train' gut immune responses may help researchers design better treatment or vaccines. 3: Do bNAbs affect the HIV reservoir in the gut? Studying resting HIV reservoir containing cells is challenging, as most contain defective HIV DNA and only about 1% contain intact HIV DNA. Cells containing intact HIV DNA are likely the source of rebound virus when ART is stopped. I will improve an existing intact HIV DNA test to sort intact from defective HIV DNA in the rectal tissue for analysis. This test will provide a more accurate, in-depth analysis of the HIV reservoir. Using the improved test, I will be able to map how the resting HIV reservoir has changed after being exposed to bNAbs. By comparing samples from the same individual, I can test if the viral reservoir has grown during ART interruption, and if bNAbs has an impact on the HIV reservoir.Findings from this project will provide insight into how the bNAbs work in the gut, and aid development of bNAbs and other strategies to eradicate the gut HIV reservoir.

抗逆转录病毒治疗（ART）提高了艾滋病毒感染者的生存率。但它不能治愈艾滋病病毒，因为ART不能从含有处于静止状态的病毒的细胞中清除艾滋病病毒，这种细胞被称为艾滋病病毒库。目前的ART选择通常需要每日口服药物，挑战包括长期副作用，治疗疲劳，耐药性和费用。广泛中和抗体（bNAb）是一种新型的HIV治疗方法，可以提供一种安全、有效和长效的ART替代品。早期研究表明，bNAb可以“训练”免疫系统，导致持久的HIV特异性反应。在SHIV感染早期给予bNAbs的猴子，表现出长达4年的病毒控制。在一项小型人类研究中，两名接受bNAb治疗的个体意外地继续保持血液中不可检测的病毒水平，甚至超过30周。然而，这些研究并不是随机的，人体内最大的艾滋病病毒库是肠道。它可以比血液中的大5倍。目前还不确定bNAb是否会进入肠道组织以及血液中。肠道中的免疫反应在许多方面也不同于血液，例如即使在开始ART后恢复较慢。最后，我们不知道bNAb如何影响肠道HIV库。RIO试验是一项正在进行的资助研究。它比较了单剂量的两种类型的bNAb与非活性药物（安慰剂）。然后，参与者停止ART，并将返回进行频繁的病毒载量测试。当血液中检测到病毒时，他们将重新开始ART。接受安慰剂的受试者将在重新开始ART后给予bNAb。RIO试验提供了一个独特的机会，通过直肠活检研究bNAb对肠道免疫系统和HIV储库的影响。我将研究RIO受试者接受研究药物前后的直肠活检样本（见附件1）。这些小的3毫米活检是由一个有经验的临床医生通过一个安全和无痛的程序在临床上收集，使用一个短的塑料管在他们的直肠。该项目旨在回答3个研究问题：1：肠道中的bNAb水平与血液中的bNAb水平相当吗？配对的直肠组织和血液bNAb水平将使用高度敏感的测试来测量，该测试甚至可以测量存在的bNAb的单个分子。如果肠道组织bNAb峰值浓度与血液相当，这些数据将支持进一步研究bNAb根除HIV肠道储库。这项工作将在预期的n = 10名受试者中进行，这些受试者在主研究中随机接受bNAb。2：bNAb会“训练”肠道中的免疫细胞吗？我将使用荧光抗体“染料”通过自动显微镜在活检切片中寻找bNAb和免疫细胞的存在。如果bNAb可以“训练”HIV特异性免疫反应，我们将有望在称为生发中心的免疫细胞区域看到bNAb。了解bNAb如何“训练”肠道免疫反应可能有助于研究人员设计更好的治疗或疫苗。3：bNAb是否影响肠道中的HIV储库？研究含有细胞的休眠HIV储库具有挑战性，因为大多数含有缺陷的HIV DNA，只有约1%含有完整的HIV DNA。当ART停止时，含有完整HIV DNA的细胞可能是反弹病毒的来源。我将改进现有的完整的HIV DNA测试，从直肠组织中的缺陷HIV DNA中分离出完整的HIV DNA进行分析。这项测试将提供一个更准确，深入的分析艾滋病毒水库。使用改进的测试，我将能够绘制出暴露于bNAb后，休眠的HIV储库如何变化。通过比较来自同一个体的样本，我可以测试在ART中断期间病毒储库是否生长，以及bNAbs是否对HIV储库有影响。该项目的发现将深入了解bNAbs如何在肠道中工作，并有助于开发bNAbs和其他根除肠道HIV储库的策略。