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HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: An observational study
PLOS Medicine ( IF 15.8 ) Pub Date : 2017-11-07 , DOI: 10.1371/journal.pmed.1002417
Timothy J Henrich 1 , Hiroyu Hatano 2 , Oliver Bacon 2, 3 , Louise E Hogan 1 , Rachel Rutishauser 1, 2 , Alison Hill 4 , Mary F Kearney 5 , Elizabeth M Anderson 5 , Susan P Buchbinder 2, 3 , Stephanie E Cohen 2, 3 , Mohamed Abdel-Mohsen 2, 6 , Christopher W Pohlmeyer 7 , Remi Fromentin 8 , Rebecca Hoh 2 , Albert Y Liu 2, 3 , Joseph M McCune 1 , Jonathan Spindler 5 , Kelly Metcalf-Pate 7 , Kristen S Hobbs 1 , Cassandra Thanh 1 , Erica A Gibson 1 , Daniel R Kuritzkes 9, 10 , Robert F Siliciano 11, 12 , Richard W Price 13 , Douglas D Richman 14, 15 , Nicolas Chomont 8 , Janet D Siliciano 10 , John W Mellors 16 , Steven A Yukl 17, 18 , Joel N Blankson 7 , Teri Liegler 2 , Steven G Deeks 2
Affiliation  

Background

It is unknown if extremely early initiation of antiretroviral therapy (ART) may lead to long-term ART-free HIV remission or cure. As a result, we studied 2 individuals recruited from a pre-exposure prophylaxis (PrEP) program who started prophylactic ART an estimated 10 days (Participant A; 54-year-old male) and 12 days (Participant B; 31-year-old male) after infection with peak plasma HIV RNA of 220 copies/mL and 3,343 copies/mL, respectively. Extensive testing of blood and tissue for HIV persistence was performed, and PrEP Participant A underwent analytical treatment interruption (ATI) following 32 weeks of continuous ART.

Methods and findings

Colorectal and lymph node tissues, bone marrow, cerebral spinal fluid (CSF), plasma, and very large numbers of peripheral blood mononuclear cells (PBMCs) were obtained longitudinally from both participants and were studied for HIV persistence in several laboratories using molecular and culture-based detection methods, including a murine viral outgrowth assay (mVOA). Both participants initiated PrEP with tenofovir/emtricitabine during very early Fiebig stage I (detectable plasma HIV-1 RNA, antibody negative) followed by 4-drug ART intensification. Following peak viral loads, both participants experienced full suppression of HIV-1 plasma viremia. Over the following 2 years, no further HIV could be detected in blood or tissue from PrEP Participant A despite extensive sampling from ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cell subsets, and plasma. No HIV was detected from tissues obtained from PrEP Participant B, but low-level HIV RNA or DNA was intermittently detected from various CD4+ T cell subsets. Over 500 million CD4+ T cells were assayed from both participants in a humanized mouse outgrowth assay. Three of 8 mice infused with CD4+ T cells from PrEP Participant B developed viremia (50 million input cells/surviving mouse), but only 1 of 10 mice infused with CD4+ T cells from PrEP Participant A (53 million input cells/mouse) experienced very low level viremia (201 copies/mL); sequence confirmation was unsuccessful. PrEP Participant A stopped ART and remained aviremic for 7.4 months, rebounding with HIV RNA of 36 copies/mL that rose to 59,805 copies/mL 6 days later. ART was restarted promptly. Rebound plasma HIV sequences were identical to those obtained during acute infection by single-genome sequencing. Mathematical modeling predicted that the latent reservoir size was approximately 200 cells prior to ATI and that only around 1% of individuals with a similar HIV burden may achieve lifelong ART-free remission. Furthermore, we observed that lymphocytes expressing the tumor marker CD30 increased in frequency weeks to months prior to detectable HIV-1 RNA in plasma. This study was limited by the small sample size, which was a result of the rarity of individuals presenting during hyperacute infection.

Conclusions

We report HIV relapse despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete or complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission. However, the small numbers of latently infected cells in individuals treated during hyperacute infection may be associated with prolonged ART-free remission.



中文翻译:

在急性 HIV-1 感染期间极早开始抗逆转录病毒治疗 (ART) 后 HIV-1 的持续存在:一项观察性研究

背景

目前尚不清楚极早开始抗逆转录病毒治疗 (ART) 是否会导致长期无抗逆转录病毒疗法的 HIV 缓解或治愈。因此,我们研究了从暴露前预防 (PrEP) 计划招募的 2 个人,他们开始预防性 ART 大约 10 天(参与者 A;54 岁男性)和 12 天(参与者 B;31 岁)男性)感染后血浆 HIV RNA 峰值分别为 220 拷贝/mL 和 3,343 拷贝/mL。对血液和组织的 HIV 持续性进行了广泛的测试,并且 PrEP 参与者 A 在连续 32 周的 ART 后经历了分析性治疗中断 (ATI)。

方法和发现

从两名参与者身上纵向获取结直肠和淋巴结组织、骨髓、脑脊液 (CSF)、血浆和大量外周血单核细胞 (PBMC),并在几个实验室中使用分子和培养研究了 HIV 的持续性——基于检测方法,包括鼠病毒生长测定 (mVOA)。两名参与者在非常早期的 Fiebig I 期(可检测到血浆 HIV-1 RNA,抗体阴性)开始使用替诺福韦/恩曲他滨进行 PrEP,然后是 4 种药物 ART 强化。在达到病毒载量峰值后,两名参与者都经历了 HIV-1 血浆病毒血症的完全抑制。在接下来的 2 年里,尽管从回肠、直肠、淋巴结、骨髓、脑脊液、循环 CD4+ T 细胞亚群和血浆。从 PrEP 参与者 B 获得的组织中未检测到 HIV,但从各种 CD4+ T 细胞亚群中间歇性地检测到低水平的 HIV RNA 或 DNA。在人源化小鼠生长试验中,从两名参与者身上检测了超过 5 亿个 CD4+ T 细胞。注射了来自 PrEP 参与者 B 的 CD4+ T 细胞的 8 只小鼠中有 3 只出现了病毒血症(5000 万输入细胞/存活小鼠),但 10 只注射了来自 PrEP 参与者 A 的 CD4+ T 细胞(5300 万输入细胞/小鼠)的小鼠中只有 1 只出现了非常严重的病毒血症低水平病毒血症(201 拷贝/毫升);序列确认不成功。PrEP 参与者 A 停止 ART 并保持无贫血状态 7.4 个月,随着 HIV RNA 的反弹,36 拷贝/毫升,6 天后上升至 59,805 拷贝/毫升。ART 迅速重启。反弹血浆 HIV 序列与通过单基因组测序在急性感染期间获得的序列相同。数学模型预测,在 ATI 之前,潜在的储库大小约为 200 个细胞,并且只有大约 1% 的具有类似 HIV 负担的个体可以实现终生无 ART 缓解。此外,我们观察到表达肿瘤标志物 CD30 的淋巴细胞在血浆中可检测到 HIV-1 RNA 之前的数周到数月内增加。这项研究受到样本量小的限制,这是由于在超急性感染期间出现的个体很少见。数学模型预测,在 ATI 之前,潜在的储库大小约为 200 个细胞,并且只有大约 1% 的具有类似 HIV 负担的个体可以实现终生无 ART 缓解。此外,我们观察到表达肿瘤标志物 CD30 的淋巴细胞在血浆中可检测到 HIV-1 RNA 之前的数周到数月内增加。这项研究受到样本量小的限制,这是由于在超急性感染期间出现的个体很少见。数学模型预测,在 ATI 之前,潜在的储库大小约为 200 个细胞,并且只有大约 1% 的具有类似 HIV 负担的个体可以实现终生无 ART 缓解。此外,我们观察到表达肿瘤标志物 CD30 的淋巴细胞在血浆中可检测到 HIV-1 RNA 之前的数周到数月内增加。这项研究受到样本量小的限制,这是由于在超急性感染期间出现的个体很少见。

结论

尽管在可能的急性 HIV 感染的最早阶段之一开始了 ART,但我们报告了 HIV 复发。血液和组织中可检测到的 HIV 几乎完全或完全消失并不会导致无限期的无抗病毒治疗的 HIV 缓解。然而,在超急性感染期间接受治疗的个体中的少量潜伏感染细胞可能与延长的无抗逆转录病毒治疗缓解期有关。

更新日期:2017-12-01
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