MICA: ERADICATE HIV-1: TARGETING THE HIV-1 RESERVOIR WITH NEW IMMUNOTHERAPEUTIC STRATEGIES

MICA：根除 HIV-1：以新的免疫治疗策略瞄准 HIV-1 病毒库

• 批准号: MR/L006588/1
• 负责人: Alexander Frater
• 金额: $ 187.07万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL006588%2F1
• 关键词: MICA; ERADICATE; HIV; TARGETING; RESERVOIR

There is no cure or vaccine for HIV infection. My aim is to explore new strategies for finding a cure for HIV infection. Thirty four million people are estimated to be infected with HIV - nearly 1% of the global adult population. Of these, 8 million are in receipt of antiretroviral therapy (also called 'ART'), but provision of ART to all who need it is a major logistical and financial challenge. Not only do patients have to stay on therapy for the rest of their lives, but there is the risk of drug resistance, side effects and stigma. We are also starting to learn that patients on ART develop other illnesses - such as heart disease, cancers and early dementia - that we do not fully understand. There is a growing understanding that although current HIV therapies have saved millions of lives, sustaining this for the future may demand new strategies. The most challenging of these is to find a cure for HIV.HIV spreads widely in the human body in the first days after infection. Upon the use of potent ART the amount of residual virus declines dramatically. However, despite many years of continuous treatment the population of infected cells does not disappear completely - there is a 'reservoir' of infected cells. This tiny but dangerous reservoir of cells has the capacity to grow out and restore the original disease state. If all infected cells could be eradicated this would constitute a cure, but this has only been achieved in one individual and involved the radical step of bone marrow transplantation as well as potent chemotherapy - not a solution applicable to the millions of infected people. The research will tackle key questions that need to be answered to achieve a cure for HIV. Can we wake up this 'reservoir' of infected cells so that the immune system can attack them? What is the best way to measure the 'reservoir' to assess if a patient might be cured? Are there patients who are more amenable to cure than others - in particular does treatment given very early after infection result in a period of 'remission' in which the patients can stop the drugs without the virus coming back?The answer to any of these will impact the field significantly. The research will be carried out by Dr John Frater and his team at the University of Oxford, collaborating with researchers across the UK and internationally. The research will be a mixture of laboratory experiments to see how infected cells behave under different conditions and clinical studies in which samples from patients will be tested to try and understand how best to target the reservoir of persisting infected cells.The studies will be conducted in three related workstreams. In the first, the researchers will study whether cells that contain silenced or 'latent' HIV can be 'woken up' using drugs normally used for cancer and whether the immune system will be able to recognise them. In the second workstream, a new test will be developed for measuring the reservoir using a combination of two techniques - one to measure the amount of viral DNA in the infected cells, and the other to use new genetic technologies to infer whether the viral genes can produce viable replicating viruses. Our aim is to develop and apply the technique, with the potential to bring it into clinical practice. Finally, in the third workstream, the researchers will develop new cohorts of patients treated very early in infection. Early treatment may be a key part of any cure, as the reservoir of infected cells at this stage looks more susceptible to new therapies. By developing these cohorts of adults and children, I aim to provide a platform to do this and conduct tests to see whether a cure might be feasible.In summary, the research comprises an exciting series of objectives. The need for an HIV cure is great, and if proof-of-principle can be gained in any of these key directions, it would be a major step forward.

HIV 感染没有治愈方法或疫苗。我的目标是探索治疗艾滋病毒感染的新策略。据估计，有 3400 万人感染了艾滋病毒——接近全球成年人口的 1%。其中，800 万人正在接受抗逆转录病毒治疗（也称为“ART”），但向所有需要的人提供 ART 是一项重大的后勤和财务挑战。患者不仅必须终生接受治疗，而且还存在耐药性、副作用和耻辱的风险。我们还开始了解到，接受 ART 治疗的患者会患上其他我们尚不完全了解的疾病，例如心脏病、癌症和早期痴呆症。人们越来越认识到，尽管目前的艾滋病毒疗法已经挽救了数百万人的生命，但未来维持这种状态可能需要新的策略。其中最具挑战性的是找到艾滋病毒的治疗方法。艾滋病毒在感染后的最初几天内会在人体内广泛传播。使用有效的抗逆转录病毒疗法后，残留病毒的数量急剧下降。然而，尽管经过多年的连续治疗，受感染细胞群并没有完全消失——存在受感染细胞的“储存库”。这个微小但危险的细胞库有能力生长并恢复原始疾病状态。如果所有受感染的细胞都能被根除，这将构成一种治愈方法，但这仅在一个人身上实现，并且涉及骨髓移植和有效化疗的根本步骤——这不是适用于数百万感染者的解决方案。该研究将解决治愈艾滋病毒所需解决的关键问题。我们能否唤醒受感染细胞的“储存库”，以便免疫系统能够攻击它们？测量“储库”以评估患者是否可以治愈的最佳方法是什么？是否存在比其他患者更容易治愈的患者 - 特别是在感染后很早就给予的治疗是否会导致一段“缓解”期，在此期间患者可以停止药物而不会感染病毒？对这些问题的答案将是领域影响显着。这项研究将由约翰·弗雷特博士和他在牛津大学的团队与英国和国际各地的研究人员合作进行。该研究将结合实验室实验和临床研究，以观察受感染细胞在不同条件下的表现，其中将测试来自患者的样本，以尝试了解如何最好地针对持续感染细胞的储存库。这些研究将在三个相关的工作流程。首先，研究人员将研究是否可以使用通常用于癌症的药物“唤醒”含有沉默或“潜伏”艾滋病毒的细胞，以及免疫系统是否能够识别它们。在第二个工作流程中，将开发一种新的测试，结合两种技术来测量储存库——一种是测量受感染细胞中的病毒 DNA 量，另一种是使用新的基因技术来推断病毒基因是否可以产生有活力的复制病毒。我们的目标是开发和应用该技术，并有可能将其应用于临床实践。最后，在第三个工作流程中，研究人员将开发新的感染早期接受治疗的患者群体。早期治疗可能是任何治疗的关键部分，因为此阶段受感染细胞的储存库看起来更容易受到新疗法的影响。通过开发这些成人和儿童群体，我的目标是提供一个平台来做到这一点并进行测试，看看治愈方法是否可行。总而言之，这项研究包括一系列令人兴奋的目标。对艾滋病毒治疗的需求是巨大的，如果能够在这些关键方向中的任何一个方面获得原理验证，那将是向前迈出的一大步。

项目成果

Managing Outbreaks of Highly Contagious Diseases in Prisons: A Systematic Review

管理监狱中高传染性疾病的爆发：系统回顾

• DOI: 10.2139/ssrn.3598874
• 发表时间: 2020
• 期刊: SSRN Electronic Journal
• 作者: Beaudry G

Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection.

• DOI: 10.1371/journal.ppat.1004954
• 发表时间: 2015-06
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Adland E;Paioni P;Thobakgale C;Laker L;Mori L;Muenchhoff M;Csala A;Clapson M;Flynn J;Novelli V;Hurst J;Naidoo V;Shapiro R;Huang KH;Frater J;Prendergast A;Prado JG;Ndung'u T;Walker BD;Carrington M;Jooste P;Goulder PJ
• 通讯作者: Goulder PJ

Managing outbreaks of highly contagious diseases in prisons: a systematic review.

• DOI: 10.1136/bmjgh-2020-003201
• 发表时间: 2020-11
• 期刊: BMJ global health
• 影响因子: 8.1
• 作者: Beaudry G;Zhong S;Whiting D;Javid B;Frater J;Fazel S
• 通讯作者: Fazel S

T-cell and antibody responses to first BNT162b2 vaccine dose in previously infected and SARS-CoV-2-naive UK health-care workers: a multicentre prospective cohort study.

• DOI: 10.1016/s2666-5247(21)00275-5
• 发表时间: 2022-01
• 期刊: The Lancet. Microbe
• 作者: Angyal A;Longet S;Moore SC;Payne RP;Harding A;Tipton T;Rongkard P;Ali M;Hering LM;Meardon N;Austin J;Brown R;Skelly D;Gillson N;Dobson SL;Cross A;Sandhar G;Kilby JA;Tyerman JK;Nicols AR;Spegarova JS;Mehta H;Hornsby H;Whitham R;Conlon CP;Jeffery K;Goulder P;Frater J;Dold C;Pace M;Ogbe A;Brown H;Ansari MA;Adland E;Brown A;Chand M;Shields A;Matthews PC;Hopkins S;Hall V;James W;Rowland-Jones SL;Klenerman P;Dunachie S;Richter A;Duncan CJA;Barnes E;Carroll M;Turtle L;de Silva TI;PITCH Consortium
• 通讯作者: PITCH Consortium