Supercharging Immune Cells May Help Control HIV Long-Term
Supercharging Immune Cells May Help Control HIV Long-Term
增强免疫细胞或有助于长期控制艾滋病毒（HIV）
A miracle cancer therapy that involves engineering a patient’s own immune cells is being repurposed for HIV, and early results from two individuals hint at its promise for long-term control of the virus. 一种涉及改造患者自身免疫细胞的奇迹癌症疗法正被重新用于治疗艾滋病毒（HIV），两名患者的早期结果暗示了该疗法在长期控制病毒方面的潜力。
As part of a clinical trial, scientists took people’s own immune cells and reprogrammed them in a lab to recognize and attack HIV in the body. After a single infusion of the modified cells, two individuals with HIV now have undetectable levels of the virus—one for nearly two years and the other for almost a year. Both have been able to go off HIV medications entirely. 作为临床试验的一部分，科学家提取了患者自身的免疫细胞，并在实验室中对其进行重编程，使其能够识别并攻击体内的艾滋病毒。在接受单次改造细胞输注后，两名艾滋病毒感染者的病毒水平已降至检测不到的程度——其中一人已持续近两年，另一人近一年。两人目前均已完全停止服用艾滋病药物。
The two people are part of a small study to test the treatment’s safety and feasibility. The initial findings were announced last week at the American Society of Gene and Cell Therapy annual meeting in Boston. 这两名患者是一项旨在测试该疗法安全性和可行性的小型研究的参与者。初步研究结果于上周在波士顿举行的美国基因与细胞治疗学会年会上公布。
“These are early days. If we can provide the proof-of-concept that this approach is both safe and effective, then there are lots of ways in which it can be optimized, to make it more affordable and scalable,” says Steven Deeks, a professor of medicine and HIV expert at the University of California, San Francisco, who led the trial. “目前还处于早期阶段。如果我们能证明这种方法既安全又有效，那么未来有很多方法可以对其进行优化，使其更具经济性和可扩展性，”加州大学旧金山分校医学教授、该试验负责人、艾滋病专家史蒂文·迪克斯（Steven Deeks）表示。
The technique, known as CAR-T cell therapy, has been used in tens of thousands of patients with tough-to-treat cancers. Half a dozen or so drugs have been approved that rely on the technique. The treatment essentially supercharges a person’s immune system to directly attack and eliminate cancer cells. Recently, it’s also been used successfully to treat severe autoimmune diseases. 这种被称为CAR-T细胞疗法的技术已应用于数万名难治性癌症患者。目前已有约六种依赖该技术的药物获得批准。该疗法本质上是增强人体的免疫系统，使其能够直接攻击并清除癌细胞。最近，它也被成功用于治疗严重的自身免疫性疾病。
“This is pretty exciting,” says Andrea Gramatica, vice president of research at amfAR, the Foundation for AIDS Research, who was not involved in the trial. “The reason this study matters and is particularly important is because it gives the HIV field a real, clinical clue that teaching the immune system to control the virus without antiretroviral therapy is achievable.” “这非常令人兴奋，”未参与该试验的美国艾滋病研究基金会（amfAR）研究副总裁安德里亚·格拉马蒂卡（Andrea Gramatica）说。“这项研究之所以重要且意义重大，是因为它为艾滋病领域提供了一个真实的临床线索：即教会免疫系统在不依赖抗逆转录病毒疗法的情况下控制病毒是可行的。”
Scientists have been pursuing a cure for HIV since the virus was first identified in the early 1980s. Antiretroviral therapy prevents the progression to AIDS by suppressing the virus to undetectable levels, but people must take medication for the rest of their lives. It has transformed HIV into a chronic condition that allows people to have a near-normal life expectancy. Yet not everyone who is HIV positive is aware of their status, and in some rural and low-income parts of the world these medications are still not widely accessible or affordable. 自20世纪80年代初首次发现艾滋病毒以来，科学家们一直在寻求治愈方法。抗逆转录病毒疗法通过将病毒抑制到检测不到的水平来防止病情发展为艾滋病，但患者必须终身服药。这种疗法已将艾滋病转变为一种慢性疾病，使患者能够拥有接近正常的预期寿命。然而，并非所有艾滋病毒感染者都了解自己的状况，在世界上一些农村和低收入地区，这些药物仍然难以获得或负担不起。
Up until now, there are under a dozen documented cases of sustained remission from HIV—known as a “functional cure” because the virus is still present in the body but is suppressed to levels that are undetectable by the immune system and HIV medication is no longer needed. 到目前为止，有记录的艾滋病毒持续缓解病例不到十二例——这被称为“功能性治愈”，因为病毒仍然存在于体内，但被抑制到免疫系统无法检测到的水平，且不再需要服用艾滋病药物。
Each of those individuals developed cancer and underwent stem cell transplantations as part of their treatment. In all but one of those cases, doctors used stem cells from donors with a rare genetic mutation called CCR5 that naturally prevents HIV from infecting healthy cells. Timothy Ray Brown, known as the “Berlin patient,” was the first known person to be cured of HIV in this way in 2008. 这些患者在治疗过程中都患上了癌症并接受了干细胞移植。除一例外，医生使用的干细胞均来自携带一种名为CCR5的罕见基因突变的捐赠者，这种突变能天然阻止艾滋病毒感染健康细胞。被称为“柏林病人”的蒂莫西·雷·布朗（Timothy Ray Brown）是2008年首位以此方式治愈艾滋病毒的已知患者。
The examples of sustained remission “have taught us that the immune system can, under the right conditions, clear HIV,” says Boro Dropulić, executive director of the Maryland nonprofit Caring Cross, who developed the CAR-T therapy for HIV. “这些持续缓解的案例告诉我们，在适当的条件下，免疫系统是可以清除艾滋病毒的，”马里兰州非营利组织Caring Cross的执行董事、艾滋病毒CAR-T疗法的开发者博罗·德罗普利奇（Boro Dropulić）表示。
But stem cell transplants aren’t scalable, he says. They’re intensive procedures that carry serious risks such as graft-versus-host disease, when the transplanted cells recognize the recipient’s cells as foreign and attack them. 但他指出，干细胞移植无法大规模推广。这些手术强度大，且伴有严重的风险，例如移植物抗宿主病，即移植的细胞将受者的细胞识别为外来物并对其进行攻击。
“What we’re trying to do is to engineer that outcome deliberately without requiring cancer, without requiring a specific donor,” Dropulić says. His organization is working on making advanced therapies like CAR-T more accessible and affordable. “我们试图做的是在不需要癌症、不需要特定捐赠者的情况下，人为地实现这一结果，”德罗普利奇说。他的组织正致力于让CAR-T等先进疗法变得更易获得且更具经济性。
Cancer and HIV are similar in that both can hide from the body’s immune system. In CAR-T therapy for cancer, patients’ T cells are engineered to express chimeric antigen receptors, or CARs, on their surface. These added receptors allow T cells to specifically identify, lock onto, and destroy cancer cells by recognizing certain antigens, or proteins, on their surface. The specific CAR that’s added depends on the type of cancer being treated. 癌症和艾滋病毒的相似之处在于，两者都能躲避人体的免疫系统。在癌症的CAR-T疗法中，患者的T细胞被改造，使其表面表达嵌合抗原受体（CAR）。这些添加的受体使T细胞能够通过识别癌细胞表面的特定抗原（蛋白质）来特异性地识别、锁定并摧毁癌细胞。所添加的特定CAR取决于所治疗癌症的类型。
Dropulić and his team engineered patients’ T cells to recognize two different sites on the HIV virus, making it more difficult for the virus to escape. “Our goal is that these cells remain like sentries in the body,” he says. “Whenever these embers of the virus start replicating, these cells are there in order to immediately take care of them.” 德罗普利奇及其团队改造了患者的T细胞，使其能够识别艾滋病毒上的两个不同位点，从而使病毒更难逃脱。“我们的目标是让这些细胞像哨兵一样留在体内，”他说。“每当这些病毒的余烬开始复制时，这些细胞就会立即将其清除。”
The trial included nine total participants who were all on antiretroviral therapy before getting the infusion of cells. A first group of three received only the CAR-T cells and were not pretreated with a conditioning drug that helps the infused cells expand and work effectively. This was an early safety test, and their HIV levels rebounded within a few weeks as expected. 该试验共包括九名参与者，他们在接受细胞输注前均在接受抗逆转录病毒治疗。第一组的三名参与者仅接受了CAR-T细胞，未预先使用有助于输注细胞扩增和有效发挥作用的预处理药物。这是一项早期的安全性测试，正如预期的那样，他们的艾滋病毒水平在几周内出现了反弹。
The other six volunteers received either a lower or higher dose of CAR-T cells, plus the conditioning drug. Three people who had started antiretroviral treatment late in their HIV infection all experienced rapid rebound of the virus and needed to go back on medication. Three people who began antiretrovirals soon after their HIV diagnosis fared better, including the two who still had viral suppression at 10 and 20 months. (The other person was able to suppress the virus for two months before rebounding.) 另外六名志愿者接受了低剂量或高剂量的CAR-T细胞，并配合了预处理药物。三名在感染后期才开始抗逆转录病毒治疗的参与者均出现了病毒快速反弹，需要恢复服药。三名在确诊后不久就开始抗逆转录病毒治疗的参与者情况较好，其中包括两名在10个月和20个月时仍保持病毒抑制状态的患者。（另一名患者在反弹前成功抑制病毒两个月。）
Even if the new technique works on more patients, it will likely be years before it’s widely available. To get the needed T cells for the treatment, patients need to undergo a procedure in which large volumes of their blood are filtered through a machine. The cells are then sent to a special lab so that they can be made into CAR-T cells, a process that takes several weeks. In the US, approved CAR-T therapies range from $300,000 to $475,000, a price tag that would make it inaccessible. 即使这项新技术在更多患者身上奏效，距离其广泛应用可能还需要数年时间。为了获得治疗所需的T细胞，患者需要接受一项程序，即通过机器过滤大量血液。随后，这些细胞被送往专门的实验室制造成CAR-T细胞，这一过程需要数周时间。在美国，已获批的CAR-T疗法费用在30万至47.5万美元之间，这一高昂的价格使其难以普及。