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.

没有治疗艾滋病毒感染或疫苗。我的目的是探索寻找治愈艾滋病毒感染的新策略。据估计，有300万人感染了艾滋病毒 - 几乎占全球成年人口的1％。其中，有800万是接受抗逆转录病毒疗法（也称为“艺术”），但向所有需要它的人提供艺术是主要的后勤和财务挑战。患者不仅必须在余生中继续接受治疗，而且存在耐药性，副作用和污名的风险。我们还开始了解到，我们对艺术的患者患有其他疾病（例如心脏病，癌症和早期痴呆症），但我们不完全了解。越来越多的理解是，尽管当前的艾滋病毒疗法已经挽救了数百万的生命，但为未来而维持这一生命可能需要新的策略。其中最具挑战性的是在感染后的头几天找到治愈艾滋病毒的治疗方法。使用有效的艺术后，残留病毒的数量急剧下降。但是，尽管经过多年的连续治疗，但感染细胞的种群并未完全消失 - 有一个“储层”感染细胞。这种细胞的微小但危险的储层具有长大和恢复原始疾病状态的能力。如果可以消除所有感染的细胞，这将构成一种治愈方法，但这仅在一个个体中实现，涉及骨髓移植的根本步骤以及有效的化学疗法 - 不是适用于数百万受感染者的解决方案。这项研究将解决需要回答的关键问题，以实现艾滋病毒的治疗方法。我们可以唤醒这种感染细胞的“储层”，以便免疫系统可以攻击它们吗？测量“水库”评估患者是否可以治愈的最佳方法是什么？是否有比其他患者更适合治愈的患者 - 特别是在感染后很早就给予治疗，导致“缓解”时期，患者可以在没有病毒后就可以停止药物？这些方法会对这些领域产生重大影响。这项研究将由约翰·弗雷特（John Frater）博士及其团队在牛津大学（University of Oxford）进行，并与英国和国际上的研究人员合作。这项研究将是实验室实验的混合物，以了解感染细胞在不同条件和临床研究中的表现如何，其中将测试来自患者的样本，以尝试最好地靶向持续感染的细胞的储层。该研究将在三个相关的工作流中进行。首先，研究人员将使用通常用于癌症的药物“唤醒”的细胞是否可以“唤醒”，以及免疫系统是否能够识别它们。在第二个工作流中，将开发一项新的测试，以使用两种技术的组合来测量储层 - 一种用于测量感染细胞中病毒DNA的量，另一个用于使用新的基因技术来推断病毒基因是否可以产生可行的复制病毒。我们的目的是开发和运用该技术，有可能将其带入临床实践。最后，在第三个工作流中，研究人员将在感染初期开发新的患者队列。早期治疗可能是任何治愈方法的关键部分，因为此阶段被感染细胞的储层看起来更容易受到新疗法的影响。通过开发这些人群和儿童，我的目标是提供一个平台来进行此操作并进行测试，以查看治疗是否可能是可行的。总而言之，该研究包括一系列令人兴奋的目标。对艾滋病毒治愈的需求是很大程度上的，如果可以在这些关键方向中获得原理证明，那将是前进的重要一步。

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