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

目前还没有治疗艾滋病毒感染的方法或疫苗。我的目标是探索新的策略，找到治愈艾滋病毒感染的方法。据估计，有3400万人感染了艾滋病毒，占全球成年人口的近1%。其中，800万人正在接受抗逆转录病毒疗法（也称为“抗逆转录病毒疗法”），但向所有需要者提供抗逆转录病毒疗法是一项重大的后勤和财政挑战。患者不仅必须在余生中继续接受治疗，而且还有耐药性、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疾病，如心脏病、癌症和早期痴呆症，这些我们还不完全了解。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，但要在未来维持这一点，可能需要新的战略。其中最具挑战性的是找到治愈艾滋病毒的方法。艾滋病毒在感染后的头几天在人体内广泛传播。在使用有效的ART后，残留病毒的量急剧下降。然而，尽管经过多年的持续治疗，感染细胞的群体并没有完全消失-存在感染细胞的“水库”。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，这将构成治愈，但这只在一个人身上实现，涉及骨髓移植和强效化疗的根本步骤-而不是适用于数百万受感染者的解决方案。这项研究将解决治愈艾滋病毒所需回答的关键问题。我们能唤醒这个受感染细胞的“水库”，以便免疫系统可以攻击它们吗？什么是测量“水库”的最佳方法，以评估患者是否可以治愈？是否有患者比其他人更容易治愈-特别是在感染后非常早期给予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出现病毒复发？任何一个问题的答案都将对该领域产生重大影响。这项研究将由牛津大学的John Frater博士和他的团队与英国和国际上的研究人员合作进行。这项研究将是一个实验室实验的混合体，以观察感染细胞在不同条件下的行为，以及临床研究，其中将测试患者的样本，以试图了解如何最好地靶向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中进行。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”HIV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，用于使用两种技术的组合来测量水库-一种是测量感染细胞中病毒DNA的量，另一种是使用新的遗传技术来推断病毒基因是否可以产生可行的复制病毒。我们的目标是开发和应用这项技术，并有可能将其投入临床实践。最后，在第三个工作流程中，研究人员将开发新的感染早期治疗患者队列。早期治疗可能是任何治愈的关键部分，因为在这个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的队列，我的目标是提供一个平台来做到这一点，并进行测试，看看治愈是否可行。总之，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，如果在这些关键方向中的任何一个方向上都能获得原理证明，这将是向前迈出的重要一步。

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.