Evidence for HIV-1 cure after CCR5Δ32/Δ32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: a case report.
Evidence for HIV-1 cure after CCR5Δ32/Δ32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: a case report.
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DOI：
10.1016/s2352-3018(20)30069-2
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发表时间：
2020-05
期刊：
影响因子：
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通讯作者：
Olavarria E
中科院分区：
文献类型：
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作者：
Gupta RK;Peppa D;Hill AL;Gálvez C;Salgado M;Pace M;McCoy LE;Griffith SA;Thornhill J;Alrubayyi A;Huyveneers LEP;Nastouli E;Grant P;Edwards SG;Innes AJ;Frater J;Nijhuis M;Wensing AMJ;Martinez-Picado J;Olavarria E
伦敦患者(IciStem队列中的36名参与者)接受了异基因干细胞移植，移植的细胞不表达CCR5(CCR5Δ32/Δ32)；在分析治疗中断后18个月报告缓解。在这里，我们介绍了这位患者的长期数据(ATI后长达30个月)，包括从不同的HIV-1储存点采集样本。我们使用超灵敏的血浆、精液和脑脊液(CSF)样本的病毒载量分析来检测HIV-1RNA。在肠道活检组织和淋巴结组织中，使用滴状数字聚合酶链式反应(DdPCR)和实时定量聚合酶链式反应(QRT)对多次重复的细胞拷贝数和总HIV-1DNA水平进行定量。我们还使用针对包装信号(ψ)和包膜(Env)的多重ddPCR分析了完整的前病毒DNA的存在。我们做了细胞内细胞因子染色来测量HIV-1特异性T细胞反应。我们使用低敏感性和低亲和力抗体分析来测量对HIV-1的体液反应。我们使用数学模型和推理方法预测了反弹的概率。伦敦患者血浆中的HIV-1病毒载量在长达30个月的时间里仍未被检测到(最后一次检测是在2020年3月4日)，检测下限为每毫升1个拷贝。患者28个月时CD_4细胞计数为430个/μ，L(23.5%)。28个月时，外周CD4记忆细胞中记录到了HIV-1DNA的非常低水平的阳性信号。21个月时，精液中的病毒载量在血浆(检测下限为每毫升12个拷贝)和细胞(检测下限为每106个细胞10个拷贝)中均未检测到。在25个月时，脑脊液在正常参数范围内，HIV-1RNA低于检测下限(每毫升LLD 1拷贝)。22个月龄时，直肠、盲肠、乙状结肠和回肠末端组织中的HIV-1 DNA检测均为阴性。27个月时腋窝淋巴结组织长末端重复序列(33拷贝/10~6细胞)和包膜病毒(26·1拷贝/10~6细胞)阳性，ψ和整合酶阴性，完整的前病毒DNA检测阴性。HIV-1特异性的CD4和CD8 T细胞反应在27个月后仍未出现。低亲和力的Env抗体继续下降。数学模型表明，在供体嵌合率为80%的情况下，终身缓解(治愈)的概率为98%，而在供体嵌合体为90%的情况下，终身缓解的概率大于99%。这名伦敦患者已经在HIV-1缓解期30个月了，在血液、脑脊液、肠道组织或淋巴组织中没有检测到具有复制能力的病毒。供体嵌合体在外周T细胞中保持在99%。我们认为这些发现代表了HIV-1的治愈。惠康信托和AMFAR(美国艾滋病研究基金会)。
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. 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. 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. 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. Wellcome Trust and amfAR (American Foundation for AIDS Research).