Evidence for HIV-1 cure after CCR5Δ32/Δ32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: a case report.,The Lancet HIV

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Evidence for HIV-1 cure after CCR5Δ32/Δ32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: a case report.
The Lancet HIV ( IF 12.8 ) Pub Date : 2020-03-10 , DOI: 10.1016/s2352-3018(20)30069-2
Ravindra Kumar Gupta ₁ , Dimitra Peppa ₂ , Alison L Hill ₃ , Cristina Gálvez ₄ , Maria Salgado ₅ , Matthew Pace ₆ , Laura E McCoy ₇ , Sarah A Griffith ₇ , John Thornhill ₈ , Aljawharah Alrubayyi ₆ , Laura E P Huyveneers ₉ , Eleni Nastouli ₁₀ , Paul Grant ₁₁ , Simon G Edwards ₁₂ , Andrew J Innes ₁₃ , John Frater ₁₄ , Monique Nijhuis ₉ , Anne Marie J Wensing ₉ , Javier Martinez-Picado ₁₅ , Eduardo Olavarria ₁₆

Affiliation

Department of Medicine, University of Cambridge, Cambridge, UK; Africa Health Research Institute, Durban, South Africa.
Nuffield Department of Medicine, University of Oxford, Oxford, UK; Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, London, UK.
Department for Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA.
IrsiCaixa AIDS Research Institute, Badalona, Spain; Autonomous University of Barcelona, Cerdanyola del Vallès, Spain.
IrsiCaixa AIDS Research Institute, Badalona, Spain.
Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Division of Infection and Immunity, University College London (UCL), London, UK.
Imperial College London, London, UK.
Department of Medical Microbiology, University Medical Center, Utrecht, Netherlands.
Division of Infection and Immunity, University College London (UCL), London, UK; Department of Virology, UCL Hospitals, London, UK; Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, London, UK.
Department of Virology, UCL Hospitals, London, UK.
Mortimer Market Centre, Department of HIV, Central and North West London NHS Trust, London, UK.
Imperial College London, London, UK; Imperial College NHS Healthcare Trust, Hammersmith Hospital, London, UK.
Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford National Institute for Health Research Biomedical Research Centre, Oxford, UK.
IrsiCaixa AIDS Research Institute, Badalona, Spain; University of Vic - Central University of Catalonia, Vic, Spain; Catalan Institution for Research and Advanced Studies, Barcelona, Spain.
Imperial College London, London, UK; Mortimer Market Centre, Department of HIV, Central and North West London NHS Trust, London, UK.

Background

The London patient (participant 36 in the IciStem cohort) underwent allogeneic stem-cell transplantation with cells that did not express CCR5 (CCR5Δ32/Δ32); remission was reported at 18 months after analytical treatment interruption (ATI). Here, we present longer term data for this patient (up to 30 months after ATI), including sampling from diverse HIV-1 reservoir sites.

Methods

We used ultrasensitive viral load assays of plasma, semen, and cerebrospinal fluid (CSF) samples to detect HIV-1 RNA. In gut biopsy samples and lymph-node tissue, cell-copy number and total HIV-1 DNA levels were quantified in multiple replicates, using droplet digital PCR (ddPCR) and quantitative real-time PCR. We also analysed the presence of intact proviral DNA using multiplex ddPCR targeting the packaging signal (ψ) and envelope (env). We did intracellular cytokine staining to measure HIV-1-specific T-cell responses. We used low-sensitive and low-avidity antibody assays to measure the humoral response to HIV-1. We predicted the probability of rebound using a mathematical model and inference approach.

Findings

HIV-1 viral load in plasma remained undetectable in the London patient up to 30 months (last tested on March 4, 2020), using an assay with a detection limit of 1 copy per mL. The patient's CD4 count was 430 cells per μL (23·5% of total T cells) at 28 months. A very low-level positive signal for HIV-1 DNA was recorded in peripheral CD4 memory cells at 28 months. The viral load in semen was undetectable in both plasma (lower limit of detection [LLD] <12 copies per mL) and cells (LLD 10 copies per 10⁶ cells) at 21 months. CSF was within normal parameters at 25 months, with HIV-1 RNA below the detection limit (LLD 1 copy per mL). HIV-1 DNA by ddPCR was negative in rectum, caecum, and sigmoid colon and terminal ileum tissue samples at 22 months. Lymph-node tissue from axilla was positive for the long-terminal repeat (33 copies per 10⁶ cells) and env (26·1 copies per 10⁶ cells), negative for ψ and integrase, and negative by the intact proviral DNA assay, at 27 months. HIV-1-specific CD4 and CD8 T-cell responses have remained absent at 27 months. Low-avidity Env antibodies have continued to decline. Mathematical modelling suggests that the probability of remission for life (cure) is 98% in the context of 80% donor chimerism in total HIV target cells and greater than 99% probability of remission for life with 90% donor chimerism.

Interpretation

The London patient has been in HIV-1 remission for 30 months with no detectable replication-competent virus in blood, CSF, intestinal tissue, or lymphoid tissue. Donor chimerism has been maintained at 99% in peripheral T cells. We propose that these findings represent HIV-1 cure.

Funding

Wellcome Trust and amfAR (American Foundation for AIDS Research).

中文翻译：

分析治疗中断后 30 个月，CCR5Δ32/Δ32 异体造血干细胞移植后 HIV-1 治愈的证据：病例报告。

背景

伦敦患者（IciStem 队列中的第 36 名参与者）接受了不表达 CCR5 的同种异体干细胞移植 ( CCR5 Δ32/Δ32)；分析治疗中断 (ATI) 后 18 个月报告缓解。在这里，我们提供了该患者的长期数据（ATI 后最长 30 个月），包括从不同 HIV-1 储存部位取样。

方法

我们使用血浆、精液和脑脊液 (CSF) 样本的超灵敏病毒载量检测来检测 HIV-1 RNA。使用微滴数字 PCR (ddPCR) 和定量实时 PCR，对肠道活检样本和淋巴结组织中的细胞拷贝数和总 HIV-1 DNA 水平进行多次重复定量。我们还使用针对包装信号 (ψ) 和包膜 ( env ) 的多重 ddPCR 分析了完整原病毒 DNA 的存在。我们进行细胞内细胞因子染色来测量 HIV-1 特异性 T 细胞反应。我们使用低灵敏度和低亲合力抗体测定来测量对 HIV-1 的体液反应。我们使用数学模型和推理方法来预测反弹的概率。

发现

伦敦患者血浆中的 HIV-1 病毒载量长达 30 个月（最后一次测试于 2020 年 3 月 4 日），使用检测限为每毫升 1 个拷贝的检测方法检测不到。 28 个月时，患者的 CD4 计数为 430 个细胞/μL（占总 T 细胞的 23·5%）。 28 个月时，外周 CD4 记忆细胞中记录到了非常低水平的 HIV-1 DNA 阳性信号。 21 个月时，精液中的病毒载量在两种血浆中均检测不到（检测下限[LLD] <12 id=28>6 细胞）。 25 个月时，CSF 处于正常参数范围内，HIV-1 RNA 低于检测限（LLD 1 个拷贝/mL）。 22 个月时，直肠、盲肠、乙状结肠和回肠末端组织样本中 ddPCR 检测的 HIV-1 DNA 呈阴性。来自腋窝的淋巴结组织长末端重复序列（每 10 ⁶个细胞 33 个拷贝）和env （每 10 ^{6 个}细胞 26·1 个拷贝）呈阳性，ψ 和整合酶呈阴性，完整原病毒 DNA 测定呈阴性， 27个月大时。 HIV-1 特异性 CD4 和 CD8 T 细胞反应在 27 个月时仍然不存在。低亲和力 Env 抗体持续下降。数学模型表明，在总 HIV 靶细胞中供体嵌合度为 80% 的情况下，终身缓解（治愈）的概率为 98%，而在供体嵌合度为 90% 的情况下，终生缓解（治愈）的概率大于 99%。