确认!人类历史上第二例艾滋病治愈者出现

全球第二例治愈病例诞生。人类屡战屡败的艰辛抗艾之路,终于迎来远方星光微现。

在大约 1 年前,一则消息曾让全世界为之振奋:在伦敦大学研究人员的帮助下,一名伦敦男子在接受干细胞移植后其艾滋病可能被治愈,检测结果显示,这名患者体内已经不存在艾滋病病毒,且已经停服抗病毒逆转录药物长达 20 个月。这是继全球首位被治愈的 “柏林病人” 之后,第二例艾滋病 “长期缓解” 的患者,也被称为“伦敦病人”。

现在,就在 3 月 10 日发布于《柳叶刀艾滋病》杂志的一篇论文中 (http://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(20)30069-2/fulltext),研究人员确认,这名 “伦敦病人” 不仅在血液中未发现可检测的活性病毒(能够复制的病毒),而且在其脑脊液、肠道、精子和淋巴结中均未发现 HIV 病毒。

由此,对该病例 “长期缓解” 的描述走向了“治愈”。正如团队在文章中所言:“我们认为这些发现代表了 HIV-1 的治疗方法。”

这意味着,全球第二例治愈病例诞生。人类屡战屡败的艰辛抗艾之路,终于迎来远方星光微现。

确认!人类历史上第二例艾滋病治愈者出现

图丨本次论文(来源:《柳叶刀艾滋病》)

两例治愈都指向 CCR5 基因

这名 “伦敦患者” 名为 Adam Castillejo。

确认!人类历史上第二例艾滋病治愈者出现

图丨 Adam Castillejo(来源:NYT)

现年 40 岁的他在接受《纽约时报》采访时公开了自己的身份,于 2003 年感染艾滋病毒。2012 年,他又被诊断出患有霍奇金淋巴瘤,随后接受了干细胞移植。

至关重要的是,治疗团队为他选择的供体,其干细胞具有两个拷贝的突变,发育成的白细胞对 HIV 具有抗性。

这一点和第一位被治愈的柏林病人 Timothy Ray Brown 的遭遇颇为相似。两位患者进行骨髓移植的主要目的都是为了白血病治疗,但医生们在治疗时选择了具有 CCR5 基因突变的骨髓捐献者。

确认!人类历史上第二例艾滋病治愈者出现

图丨 “柏林病人” Timothy Ray Brown(来源:equal)

大名鼎鼎的 CCR5,自 1996 年被首次发现以来,科学家们逐渐意识到其在艾滋病病毒感染过程中发挥的 “帮凶” 作用。作为 CCR5 基因编码的一种蛋白质,CCR5 定位于白细胞表面,作为趋化因子的受体而与免疫系统相关,在 T 细胞与特定组织和靶器官结合过程中发挥作用,具有调控 T 细胞核单核细胞或巨噬细胞系的迁移、增殖与免疫的功能。

相关研究信息显示,当 CCR5 基因的 32 位碱基对缺失突变(CCR5△32/△32)会阻止细胞表达 CCR5 细胞因子受体,进而阻断某些 HIV 亚型病毒进入 CD4+T 细胞的途径。人群调查和实验研究结果表明,CCR5△32 缺失的个体拥有正常的免疫功能和炎症反应,并且对 HIV-1 的感染表现出显著的抵御能力,因此,作用于 CCR5 的抑制剂将有效阻断 HIV-1 病毒的感染。

在接受了干细胞移植之后,2019 年公布的治疗进展就显示,这位患者不仅癌症得到治疗,而且艾滋病毒已经缓解。但是当时,Adam Castillejo 选择保持匿名。

他告诉《纽约时报》:“我当时在看电视,感觉就像’好,他们在谈论我’。这让我觉得怪异。”

但他现在决定透露自己的身份。因为他希望自己的境遇能够给他人以乐观的支撑。Castillejo 说:“我想成为希望的一个象征。”

“只有时间才能证明一切”

根据最新的论文,Castillejo 停止使用抑制 HIV 的抗逆转录药物后 30 个月、移植后 46 个月都处于无病情的状态。

而且自 2019 上次报告以来,团队对其进行着后续的检测和跟踪,以继续确认患者体内各种组织中是否仍存在 HIV。在当时的论文中,该团队表示还不能下结论说,这位患者已经被治愈,而是更倾向于“长期缓解”,在 2 年的观察期后,才能下最终的定论。

检测显示,尽管他们在某些细胞(包括一些白细胞)中还是发现了该病毒 DNA 的痕迹,但这些痕迹并无大碍,因为它们无法产生这种病毒。

确认!人类历史上第二例艾滋病治愈者出现

图丨 Ravindra Gupta(来源:AHRI)

这项研究的第一作者、剑桥大学的 Ravindra Gupta 教授说:“我们所检测到的这些就像是化石,这些化石哪都到不了。”

研究人员报告称,计算机模型表明,在停止使用 HIV 药物 29 个月后,只要保持 90% 以上的骨髓干细胞是供体来源,Castillejo 保持不含 HIV 病毒的机会几乎是肯定的。目前,人们认为 Castillejo 的干细胞中约有 99% 来自供体。

Ravindra Gupta 说,治愈的两个案例都显著表明,或许可以借助癌症治疗方法来治疗艾滋病毒。但是,他补充说,干细胞移植不适用于大多数艾滋病毒感染者,因为它们是高风险的侵入性手术,尽管如此,这一新发现仍然重要,因为它佐证了第一个治愈案例并非昙花一现的偶然事件。

曾领导柏林病人治疗的 GeroHütter 曾表示,他同意这种(骨髓移植)治疗方法只能用于一小部分患者,但他希望伦敦病人的案例能够激发人们对以 CCR5 为目标的基因治疗的兴趣,这可能适用于更广泛的群体。

因为,从某种程度上来说,针对体细胞基因编辑的基因治疗技术已经十分成熟,且治疗成本也一定会越来越低,问题的关键在于找到要修改的目标基因和想要预防或治疗的疾病之间的明确关系,修改某个或某些基因后能否实现某种疾病的预期预防和治疗效果。很显然,柏林病人和伦敦病人在移植 CCR5 基因缺失突变捐赠者的干细胞后,体内 HIV 病毒被完全清除甚至被彻底治愈,就是最好的预示。

确认!人类历史上第二例艾滋病治愈者出现

图|who 数据显示,截至 2017 年底,全球共有 3690 万人感染艾滋病毒。据估计,全世界 15-49 岁成年人中有 0.8% 携带艾滋病毒,各国和各区域之间的艾滋病毒情况仍有很大差异。非洲区域仍然是受影响最严重的地区,每 25 名成年人中有近 1 人 (4.1%) 感染艾滋病毒,占全世界艾滋病毒感染者的近三分之二(来源:who)

不过这也只是一种可能而已。在与论文相关的一篇文章中,未参与这项工作的科学家 Jennifer Zerbato 和 Sharon Lewin 强调 (https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(20)30075-8/fulltext)指出,现在还很难确定艾滋病的治疗方法,“还需要更多治愈的患者,才能真正了解所需的随访时间以及病毒复制被延迟的可能性” 。

Lewin 说,对于 Castillejo 这个例子而言,没有任何具有活性的 HIV 病毒当然令人感到兴奋和鼓舞,但他的真正治愈是否会随着时间的流逝而出现不同的答案,仍尚未可知。

“我们很难知道答案。最终,只有时间才能证明一切”,Lewin 称,“但这看起来很有希望。”

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