HIV-1 Reservoir in Gut-Associated Lymphoid Tissue (GALT) in Primary HIV Infection

艾滋病毒是一种慢性疾病，可以通过日常药物治疗得到很好的控制，这种药物被称为抗逆转录病毒疗法(ART)。通常，抗逆转录病毒治疗不会立即开始，而是在免疫细胞(CD4T细胞)降至设定水平以下后才开始。虽然抗逆转录病毒疗法极大地提高了艾滋病毒携带者的存活率，但它不能治愈艾滋病毒，因此一旦开始治疗，就是终生的。这是因为目前的技术不能从处于静止状态的含有病毒的细胞中去除艾滋病毒--也就是众所周知的艾滋病毒储存库。因此，病毒水平会回升，如果停止抗逆转录病毒治疗，人们可能会感到不适。由于药物副作用、治疗疲劳、病毒耐药性和费用，终身抗逆转录病毒治疗是具有挑战性的。虽然单靠抗逆转录病毒疗法是不可能治愈艾滋病毒感染的，但在血液中没有检测到病毒的情况下进行一段时间的治疗可能是可行的，而且非常有吸引力。最近的研究表明，如果在一个人感染艾滋病毒后立即开始抗逆转录病毒治疗，与那些在晚期疾病开始治疗的人相比，可以获得更低水平的病毒储备库。出乎意料的是，在一些从早期感染中接受治疗的罕见个体中，即使在治疗停止后，病毒也没有恢复到高水平；这被称为治疗后控制(PTC)。使用目前的实验室测试来测量血液中的艾滋病毒蓄积量，无法准确预测谁可能实现PCT。血液测试测量病毒蓄积量可能无法准确预测PTC的一个原因可能是反弹的病毒不是来自血细胞。人体内有不同的艾滋病毒储存库，病毒可以从体内返回；最大的是肠道，它可以比血液中的储存库大五倍。据推测，ART停止后返回的病毒可能来自肠道相关淋巴组织(GalT)内的蓄水池。为了解决这个问题，我的主要目标是描述和比较肠道样本中病毒储备量的测量结果，并与那些开始早期抗逆转录病毒治疗的人的血液样本中的病毒储存量进行比较。这将是正在进行的名为Heather的治疗早期感染研究的子研究，该研究正在评估病毒库的血液生物标记物。登记参加Heather研究的参与者将被邀请另外同意进行内窥镜检查，其中将采集少量肠道样本，用于对病毒宿主的研究评估。这些活组织检查是常规程序，将由伦敦圣玛丽医院专门从事这类程序的医生进行。我们将使用牛津大学专门的实验室测试来分析血液和肠道样本，以评估组成储存库的细胞类型，以及肠道储存库中艾滋病毒的数量与血液的比较。然后，我们的目标是调查肠道储藏措施是否可以预测哪些患者可以安全地中断ART并实现PTC。最终，将通过提供中断治疗的选项来测试这一点(作为研究的一部分)，但仅限于根据我们的研究结果被认为最有可能实现PTC的极少数患者。这项工作的结果将为其他研究提供参考，这些研究测试旨在通过帮助调查人员决定谁可以停止治疗而不会再次感染艾滋病毒的新疗法。

HIV is a chronic disease that can be well controlled with daily medications, known as antiretroviral therapy (ART). Usually ART is not started straight away, but only after immune cells (CD4 T-cells) have fallen below a set level. Although ART has dramatically improved survival for people living with HIV, it cannot cure HIV and so once started, treatment is life-long. This is because current ART cannot remove HIV from cells containing virus in a resting state - known as the HIV reservoir. For this reason virus levels return and people can become unwell if ART is stopped. Lifelong ART is challenging due to drug side effects, treatment fatigue, viral drug-resistance and expense. Whilst curing HIV infection is not possible with ART alone, a period of time off treatment without detectable virus in the blood - "remission" maybe feasible and is highly attractive.Recent studies have shown that if ART is started immediately after an individual becomes infected with HIV a lower level of viral reservoir can be achieved than for those starting treatment in later stage disease. Unexpectedly, amongst some rare individuals treated from early infection, virus did not return to high levels even after therapy is stopped; this is called post-treatment control (PTC).Using current laboratory tests to measure HIV reservoir in blood cannot accurately predict who might achieve PCT. One reason blood tests measuring viral reservoir may not accurately predict PTC may be that the rebounding virus is not coming from blood cells. There are different HIV reservoirs in the body from which the virus can return; the largest is the gut which can be five times larger than the reservoir in the blood. It is hypothesized that virus that returns after ART is stopped maybe coming from reservoirs within the Gut-associated lymphoid tissue (GALT). To address this question, my key aim is to characterise and compare measures of viral reservoir in gut samples with those from blood from people who have started on early ART. This will be a sub-study of an ongoing study of treated early infection called HEATHER which is evaluating blood biomarkers of viral reservoir. Participants enrolled into the HEATHER study will be invited to additionally agree to an endoscopy where small samples of gut will be taken for research evaluation of viral reservoirs. These biopsy tests are routine procedures and will be performed by a doctor who specialises in such procedures at St Mary's Hospital in London. We will analyse the blood and gut samples using specialised laboratory tests at the University of Oxford in order to assess the types of cells which make up the reservoir and the amount of HIV in the gut reservoir compared with blood. We then aim to investigate if gut reservoir measures can predict which patients might safely interrupt ART and achieve PTC. Ultimately this will be tested by giving the option of interrupting treatment (as part of a study) but only amongst a very small number of patients deemed most likely to achieve PTC based on our study results. The results of this work will inform other studies which test new treatments aimed at curing HIV by helping the investigators to decide who can stop treatment without the virus returning.