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

原发性 HIV 感染中肠道相关淋巴组织 (GALT) 中的 HIV-1 储库

• 批准号: MR/N001265/1
• 负责人: John Thornhill
• 金额: $ 33.99万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN001265%2F1
• 关键词: HIV; Reservoir; Gut; Associated; Lymphoid

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.

艾滋病毒是一种慢性疾病，可以很好地控制与日常药物，称为抗逆转录病毒疗法（ART）。通常，ART不会立即开始，而是只有在免疫细胞（CD 4 T细胞）降至设定水平以下后才开始。虽然抗逆转录病毒疗法大大提高了艾滋病毒感染者的生存率，但它不能治愈艾滋病毒，因此一旦开始治疗，治疗是终身的。这是因为目前的ART不能从含有处于静止状态的病毒的细胞中清除HIV-称为HIV库。由于这个原因，病毒水平恢复，如果停止ART，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ART具有挑战性。虽然单靠抗逆转录病毒疗法无法治愈艾滋病病毒感染，但在一段时间内停止治疗而血液中没有检测到病毒-“缓解”可能是可行的，并且非常有吸引力。最近的研究表明，如果在感染艾滋病病毒后立即开始抗逆转录病毒疗法，可以达到比那些在晚期疾病中开始治疗的人更低的病毒储存水平。出乎意料的是，在一些罕见的早期感染治疗的个体中，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HIV储库不能准确预测谁可能达到PCT。测量病毒储库的血液测试可能无法准确预测PTC的一个原因可能是反弹的病毒不是来自血细胞。体内有不同的艾滋病毒储存库，病毒可以从其中返回;最大的是肠道，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）内的储库。为了解决这个问题，我的主要目标是验证和比较肠道样本中的病毒储存器的措施与那些从早期ART开始的人的血液中的病毒储存器的措施。这将是一项正在进行的治疗早期感染的研究的子研究，称为石楠，该研究正在评估病毒储存器的血液生物标志物。将邀请入组石楠研究的受试者额外同意进行内镜检查，其中将采集少量肠道样本用于病毒储库的研究评价。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此类程序的医生进行。我们将在牛津大学使用专门的实验室测试来分析血液和肠道样本，以评估构成水库的细胞类型以及与血液相比肠道水库中的HIV数量。然后，我们的目标是调查肠道水库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择（作为研究的一部分）来测试这一点，但仅在基于我们的研究结果被认为最有可能实现PTC的极少数患者中进行。这项工作的结果将通过帮助研究人员决定谁可以停止治疗而不返回病毒，为其他测试旨在治愈艾滋病毒的新疗法的研究提供信息。

项目成果

HIV reservoir size is determined prior to ART initiation and linked to CD8 T cell activation and memory expansion

HIV 储存库大小在 ART 开始之前确定，并与 CD8 T 细胞激活和记忆扩展相关

• DOI: 10.1101/580308
• 发表时间: 2019
• 作者: Martin G

A pilot evaluation of whole blood finger-prick sampling for point-of-care HIV viral load measurement: the UNICORN study.

• DOI: 10.1038/s41598-017-13287-2
• 发表时间: 2017-10-20
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Fidler S;Lewis H;Meyerowitz J;Kuldanek K;Thornhill J;Muir D;Bonnissent A;Timson G;Frater J
• 通讯作者: Frater J

Immunological biomarkers predict HIV-1 viral rebound after treatment interruption.

• DOI: 10.1038/ncomms9495
• 发表时间: 2015-10-09
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Hurst J;Hoffmann M;Pace M;Williams JP;Thornhill J;Hamlyn E;Meyerowitz J;Willberg C;Koelsch KK;Robinson N;Brown H;Fisher M;Kinloch S;Cooper DA;Schechter M;Tambussi G;Fidler S;Babiker A;Weber J;Kelleher AD;Phillips RE;Frater J
• 通讯作者: Frater J

Virological Blips and Predictors of Post Treatment Viral Control After Stopping ART Started in Primary HIV Infection.

• DOI: 10.1097/qai.0000000000001220
• 发表时间: 2017-02-01
• 期刊: Journal of acquired immune deficiency syndromes (1999)
• 作者: Fidler S;Olson AD;Bucher HC;Fox J;Thornhill J;Morrison C;Muga R;Phillips A;Frater J;Porter K
• 通讯作者: Porter K

Tolerability of four-drug antiretroviral combination therapy in primary HIV-1 infection.

• DOI: 10.1111/hiv.13118
• 发表时间: 2021-09
• 期刊: HIV medicine
• 影响因子: 3
• 作者: Burns JE;Stöhr W;Kinloch-De Loes S;Fox J;Clarke A;Nelson M;Thornhill J;Babiker A;Frater J;Pett SL;Fidler S
• 通讯作者: Fidler S