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清华大学张林琦教授:治愈艾滋病,难,但有希望

曼话 曼话 来源:医药魔方
2019-03-10
艾滋病
原文

HIV(黄色)感染人类免疫细胞(蓝色) 图片来源:NIH/SPL

 

艾滋病(AIDS)是人类免疫缺陷病毒(HIV)感染的最后阶段,被发现距今已有近40年,从最初的“未知恐慌”到如今的“沉着应对”,离不开抗逆转录病毒药物的成功研发。通过这类药物的“鸡尾酒”疗法,艾滋病患者体内的病毒可以得到非常好地控制,患者死亡率已经控制在5%以下,存活年限可达到与正常人相似的寿命。

 

不过,抗逆转录病毒药物并不能治愈艾滋病患者,因为,每日服用这类药物虽然几乎可以全部清除外周血中的HIV病毒,但无法杀死潜伏在宿主细胞——CD4+ T淋巴细胞中的病毒。一旦停药,这些潜伏的HIV病毒就会再次攻击机体的免疫系统。


几十年来,唯一被认定为治愈的艾滋病患者只有1位。这位昵称为“柏林病人”的美国人叫Timothy Ray Brown,他于1995年在柏林上学时感染了HIV,又于2006年被诊断出患上了急性髓系白血病。

 

TimothyRay Brown(来源:DANIEL JACK LYONS)

 

治愈白血病最有效的手段是造血干细胞移植;移植后,患者的免疫系统得以重建,就能杀死残留在体内的癌细胞(患者接受移植前,先接受放疗或化疗的预处理,以清除体内的肿瘤细胞和其它异常细胞),从而达到治愈的目的,并防止复发。

 

Brown在2007年接受了移植,不过,他的骨髓捐献者非常特别,携带一种名为CCR5的基因的突变版本——CCR5Δ32。

 

CCR5全称为C-Cchemokine receptor type 5,表达在白细胞表面,是HIV 病毒入侵机体细胞的主要辅助受体之一。当它发生突变后,病毒就无法进入细胞,从而也就无法发挥“破坏”作用。具有CCR5Δ32突变的人群对CCR5依赖型HIV病毒具有天然抵抗力。

 

这次特殊的骨髓移植创造了奇迹:Brown的白血病和艾滋病都被治愈了。他也成为世界上首位被彻底治好的艾滋病患者,停药至今也未被检测出HIV病毒。

 

由于之后很长一段时间内,没有再出现像Brown这样被治愈的成功案例,因此,很多人认为,这种“一石二鸟”的疗法不可复制。

 

图片来源:Nature

 

2019年3月5日,转机似乎出现了。

 

据Nature[1]杂志报道,一名被称为“伦敦病人”的患者在接受了近乎同样的疗法后已维持了18个月的缓解(即,血液检测未显示有病毒反弹)。

 

这位“伦敦病人”于2003年被诊断出患有艾滋病,又在2012年被诊断出患有霍奇金淋巴瘤,之后,于2016年5月接受了一名CCR5 基因突变捐赠者的造血干细胞移植,移植后继续接受抗逆转录病毒药物治疗16个月,并于2017年9月停止用药。

 

让科学家们惊喜的是,停药至今,患者血液中的HIV已经降低至不可检测的水平,且体内的白细胞不会被依赖于CCR5受体的HIV感染。

 

领导这一研究的Ravindra K Gupta表示,目前就认为“伦敦病人”被治愈还为时尚早,仍需要继续监测其病情发展。尽管如此,“伦敦病人”还是得到了国内外媒体的广泛报道。对于该病例具有怎样的意义,不少专家发表了自己的看法。

 

其中,很多人表示,尽管听起来振奋人心,但这类疗法其实有非常大的局限性,并不会成为太多艾滋病患者的治疗策略。一方面,目前,通过服药可以对HIV病毒起到很好的抑制作用,选择骨髓移植事实上是在冒更大的风险。另一方面,“伦敦病人”和“柏林病人”被成功治疗有两个不可或缺的因素:1)他们都只感染了依赖CCR5的HIV病毒;2)他们找到了天然携带CCR5Δ32的骨髓捐献者。而事实上,这两个条件都不那么容易满足。就第一个条件来说,HIV病毒还有CXCR4依赖型;就第二个条件来说,天然携带CCR5Δ32的骨髓捐献者并不“常见”,除欧洲人外,全球其它地区存在CCR5Δ32突变的人几乎为零。

 

 

不过,尽管这并不属于“广泛治愈艾滋病”方面的突破,但该病例依然有非常重要的启示作用。“柏林病人”的主治医生希望,“伦敦病人”能够唤起学界对基于CCR5的艾滋病疗法的研究热情。而清华大学艾滋病综合研究中心主任张林琦教授在接受记者采访时则表示,“伦敦病人”部分验证了“柏林病人”被治愈并非偶然,具有非常重要的“科学意义”,为通过基因编辑干细胞达到治愈艾滋病的目的提出了非常重要的参考。

 

张林琦教授告诉记者,艾滋病之所以难治,是因为HIV病毒有两个“致命”的特点,第一,它们在复制过程中会产生很多突变导致免疫系统和抗病毒药物“失活”;此外,病毒的遗传物质会整合到人类细胞的DNA中,变成宿主细胞基因组的一部分,从而无法被清除(现有的抗艾药都是要在病毒复制的时候才能发挥作用,对这些潜伏的病毒无效)。

 

HIV病毒可以通过每月注射一次药物来控制。(图片来源:NIBSC/SciencePhoto Library)

 

目前上市的抗逆转录病毒小分子药物尽管非常有效,但患者需要终身每日用药。因此,科学家们一直在寻找更好的抗艾药物。一些与其它抗逆转录病毒药物联合的、相对长效的药物于这两年获批上市,比如Trogarzo(抗体药物、两周注射一次)、艾可宁(多肽类药物;一周一次)。还有一些药物尽管还未上市,但取得了积极的研究结果,如抗逆转录病毒药物cabotegravir和rilpivirine[2]。据Nature的最新消息,1000多人参与的双胞胎试验结果表明,在预防HIV复制方面,每月注射一次这两种药物的组合可取得与每日服用三种常见的抗逆转录病毒药物相同的效果。

 

为了实现更长效地“抗艾”,领域内的很多科学家还在开发一种被称为广谱综合性抗体(broadlyneutralizing antibodies ,bNAbs)的疗法,相关成果屡屡登上顶级杂志。举例来说,去年9月26日,美国洛克菲勒大学的Michel C. Nussenzweig教授带领团队在Nature及其子刊发表了2篇重要论文。研究称,来自1b期临床试验(NCT02825797)的结果表明,两种bNAb(3BNC117+10-1074)的组合(15名参与者停止服用抗逆转录病毒药物,并在随后的6周内接受3次组合抗体的注射)在“响应者”中能够平均控制HIV病毒21周,其中一些患者能够坚持30周以上,且受试者没有出现明显的副作用[3]。此外,即便是HIV病毒血症(viremic)患者,bNAbs同样表现出了良好的治疗效果。7名受试对象中,有4名患者血液中的病毒载量得到控制,且保持了3个月的低水平[4 ]。

 

图片来源:Nature[3]

 

据张林琦教授介绍,广谱综合性抗体既能很好地抑制HIV病毒,也对提高免疫反应有很好的作用,是在领域内被普遍看好的下一代抗病毒药物,有望通过动员人体的免疫系统达到“功能性治愈”的目标。

 

所谓“功能性治愈”是指,尽管还有少量的HIV病毒存在于患者体内,但这些病毒的复制将被长久地抑制,疾病进展显著放缓,感染症状停止,患者停止用药。而真正意义的艾滋病治愈是指彻底清除HIV潜伏感染的细胞。这方面的研究进展笔者在《免疫疗法能创造治愈艾滋病的奇迹吗?》一文中曾介绍过一些。有研究已经证明,PD-1抗体可能有助于瓦解HIV的潜伏,消除HIV潜伏感染细胞[5][6]。

 

除了药物治疗,基因疗法也有望成为治愈艾滋病的有效方法。有科学家们发现,在小鼠模型中,基因魔剪CRISPR可精准“破坏”HIV的遗传物质,从而抑制其复制[7][8]。

 

张林琦教授认为,未来,大分子抗体药物、细胞治疗等新疗法的进一步研发是艾滋病治疗领域的必然趋势,其团队除了在这些方面展开研究,还将继续艾滋病预防性疫苗的开发。“我们正在对感染了HIV病毒但健康状态依然良好的一些个体的病毒、免疫系统以及基因特点进行深入研究,我们相信,这将为开发新的靶点和疗法提供重要的方向。”他说。


相关论文:

[1] Ravindra K Gupta etal. HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-celltransplantation. Nature(2019).

[2]David A Margolis et al. Long-acting intramuscular cabotegravir and rilpivirinein adults with HIV-1 infection (LATTE-2): 96-week results of a randomised,open-label, phase 2b, non-inferiority trial. The Lancet(2017).

[3] Pilar Mendoza etal. Combination therapy with anti-HIV-1 antibodies maintains viral suppression.Nature(2018).

[4] Yotam Bar-On et al.Safety and antiviral activity of combination HIV-1 broadly neutralizingantibodies in viremic individuals. Nature Medicine(2018).

[5]Rémi Fromentin et al.PD-1 blockadepotentiates HIV latency reversal ex vivo in CD4+ T cellsfromART-suppressed individuals. Nature Communications(2019).

[6]A Guihot et al.Drastic decrease of theHIV reservoir in a patient treated with nivolumab forlung cancer. Annals ofOncology(2017).

[7] Hsin-Kai Liao et al. Use of theCRISPR/Cas9 system as an intracellular defense against HIV-1 infection in humancells. Nature Communications(2015).

[8] ChaoranYin et al.In Vivo Excision of HIV-1 Provirus by saCas9 and Multiplex Single-GuideRNAs in Animal Models. Molecular Therapy(2017).

 

参考资料:

1# Secondpatient free of HIV after stem-cell therapy

2# Newresearch shows promise for immunotherapy as HIV treatment

3# Monthly HIV injectioncould free patients from gruelling drug regimen

4# 中国首个抗艾滋病一类新药艾可宁在华上市

5# FDA批准HIV治疗药物Trogarzo,每14天注射一次

6# 同登Nature、Nature医学!抗艾滋新成果,早期临床数据积极

7# 全球第二例艾滋病治愈者出现意味着什么

8# 顶级科学杂志爆大料!世界上第二例 HIV 「治愈」案例出现了


机器翻译

HIV (yellow) infection of human immune cells (blue) Image credit: NIH/SPL

AIDS is the last stage of human immunodeficiency virus (HIV) infection and has been discovered For nearly 40 years, from the initial "unknown panic" to today's "satisfaction", the successful development of antiretroviral drugs is inseparable. Through the "cocktail" therapy of these drugs, the virus in AIDS patients can be very Good control, the patient mortality rate has been controlled below 5%, and the life span can reach a life expectancy similar to that of normal people.

However, antiretroviral drugs can not cure AIDS patients because, taken daily Although these drugs can almost completely eliminate the HIV virus in the peripheral blood, they cannot kill the virus that is lurking in the host cell, CD4+ T lymphocytes. Once stopped, these latent HIV viruses will attack the body's immune system again.

For the past few decades, the only AIDS patient identified as a cure has only one. The American who is known as the "Berlin patient" is Timothy Ray Brown, who felt when he was in Berlin in 1995. HIV was diagnosed with acute myeloid leukemia in 2006.

TimothyRay Brown (Source: DANIEL JACK LYONS)

The most effective means of curing leukemia is hematopoietic stem cells. Transplantation. After transplantation, the patient's immune system can be reconstituted to kill cancer cells that remain in the body (the patient undergoes pretreatment with radiotherapy or chemotherapy before removal to remove tumor cells and other abnormal cells). Reaching the goal of healing and preventing recurrence.

Brown was transplanted in 2007, however, his bone marrow donor is very special, carrying a mutant version of the gene called CCR5 - CCR5Δ32. /p>

CCR5 is called C-Cchemokine receptor type 5 and is expressed on the surface of white blood cells. It is one of the main co-receptors of HIV virus invading the body cells. When it is mutated, the virus cannot enter the cell, thus Can't play a "destructive" role. People with CCR5Δ32 mutations are naturally resistant to CCR5-dependent HIV.

This special bone marrow transplant has created a miracle: Brown's leukemia and AIDS are cured He also became the first AIDS patient to be completely cured in the world, and he has not been tested for HIV since he stopped taking it.

Because for a long time, there is no cure like Brown. Successful cases, therefore, many people believe that this "one stone two birds" therapy can not be copied.

Source: Nature

On March 5, 2019, the transfer seems to have appeared. /p>

According to Nature[1], a patient known as the "London Patient" has maintained an 18-month remission after receiving nearly the same treatment (ie, blood tests have not shown a virus). Rebound).

The "London Patient" was diagnosed with AIDS in 2003 and was diagnosed with Hodgkin's lymphoma in 2012. He then accepted it in May 2016. A hematopoietic stem cell transplant of a CCR5 gene mutation donor, continued to receive antiretroviral therapy for 16 months after transplantation, and stopped taking the drug in September 2017.

The scientists were surprised that the stop So far, the HIV in the blood of patients has been reduced to an undetectable level, and white blood cells in the body will not be affected. HIV infection at the CCR5 receptor.

Ravindra K Gupta, who led the study, said it is still too early to think that the "London patient" has been cured, and that it still needs to continue to monitor its disease progression. Still, "London patients" have been widely reported by domestic and foreign media. Many experts have expressed their views on the significance of this case.

Among them, many people said that although it sounds exciting, However, such treatments have very limited limitations and will not become a treatment strategy for many AIDS patients. On the one hand, at present, the drug can be used to suppress HIV virus. The choice of bone marrow transplantation is actually Taking a bigger risk. On the other hand, there are two indispensable factors for successful treatment of “London patients” and “Berlin patients”: 1) they are all infected with HIV that depends on CCR5. 2) They have found natural Bone marrow donors carrying CCR5Δ32. In fact, these two conditions are not so easy to satisfy. In the first condition, the HIV virus also has a CXCR4-dependent type. In the second condition, the CCR is naturally carried. 5Δ32 bone marrow donors are not “common”. Except for Europeans, there are almost zero people with CCR5Δ32 mutations in other parts of the world.

However, although this is not a breakthrough in “wide cure for AIDS” However, the case still has a very important enlightenment. The doctor of "Berlin patient" hopes that "London patients" can evoke academic enthusiasm for research on CCR5-based AIDS therapy. Professor Zhang Linqi, director of the Center for AIDS Comprehensive Research at Tsinghua University, accepts In an interview, the reporter said that the "London Patient" part of the verification that the "Berlin patient" was cured is not accidental. It has a very important "scientific meaning" and provides a very important reference for the purpose of killing AIDS through genetically edited stem cells.

Professor Zhang Linqi told reporters that the reason why AIDS is refractory is because the HIV virus has two "fatal" characteristics. First, they will produce many mutations during the replication process, resulting in the loss of the immune system and antiviral drugs. In addition, the genetic material of the virus will be integrated into the DNA of the human cell and become the host cell genome. Part of it, so it can't be removed (the existing anti-aerobic drugs are only needed when the virus is copied, and it is not effective for these latent viruses).

HIV virus can be injected once a month. Control. (Source: NIBSC/SciencePhoto Library)

The currently marketed antiretroviral small molecule drugs are very effective, but patients need to take them daily for life. Therefore, scientists are always looking for better Anti-Ai drugs. Some are combined with other antiretroviral drugs. Relatively long-acting drugs have been approved for two years, such as Trogarzo (antibody drug. once every two weeks). Akonin (polypeptide drugs. once a week) Some drugs, although not yet on the market, have achieved positive results, such as the antiretroviral drugs cabotegravir and rilpivirine [2]. According to the latest news from Nature, more than 1,000 people participated in the twin test results showed that prevention In terms of HIV replication, a monthly combination of these two drugs can achieve the same effect as taking three common antiretroviral drugs per day.

To achieve Long-term "anti-Ai", many scientists in the field are also developing a treatment called broadlyneutralizing antibodies (bNAbs), and the results have repeatedly hit top magazines. For example, last September On the 26th, Professor Michel C. Nussenzweig of Rockefeller University in the United States led a team to publish two important papers in Nature and its sub-distribution. The study said that the results from the Phase 1b clinical trial (NCT02825797) showed that the two bNAbs (3BNC117+10- The combination of 1074) (15 participants stopped taking antiretroviral drugs and received 3 injections of the combined antibody in the next 6 weeks) was able to control the HIV virus for an average of 21 weeks in the “responders”, some of whom were able to Persist for more than 30 weeks, and the subjects did not have obvious side effects [3]. In addition, even in patients with HIV viremia, bNAbs also showed good therapeutic effects. Of the 7 subjects, 4 The viral load in the blood of patients was controlled and maintained at a low level of 3 months [4].

Source: Nature[3]

According to Professor Zhang Linqi, Broad-spectrum comprehensive resistance The body can not only effectively inhibit the HIV virus, but also has a good effect on improving the immune response. It is a next-generation antiviral drug that is generally optimistic in the field and is expected to achieve the goal of "functional cure" by mobilizing the body's immune system.

The so-called "functional cure" means that although a small amount of HIV virus is present in patients, the replication of these viruses will be suppressed for a long time, the disease progresses significantly, and the symptoms of infection stop. The patient stopped taking the drug. The true meaning of AIDS cure is to completely eliminate the cells that are latently infected by HIV. Research progress in this area. Can the immunotherapy create a miracle to cure AIDS? Some articles have been introduced in the article. Some studies have shown that PD-1 antibodies may help to disrupt the potential of HIV and eliminate HIV latent infected cells [5]. [6].

In addition to drug treatment, genes Therapy is also expected to be an effective way to cure AIDS. Some scientists have found that in the mouse model, the gene magic clip CRISPR can accurately "destroy" the genetic material of HIV, thereby inhibiting its replication [7][8].

Professor Zhang Linqi believes that in the future, the further development of new therapies such as macromolecular antibody drugs and cell therapy is an inevitable trend in the field of AIDS treatment. In addition to research in these areas, the team will continue to develop HIV preventive vaccines. We are conducting in-depth research on the virus, immune system and genetic characteristics of individuals who are infected with HIV but are still in good health. We believe this will provide an important direction for the development of new targets and therapies." He said. /p>

Related papers:

1]RavindraK Gupta etal. HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-celltransplantation. Nature(2019).

2]David AMargolis et Al. Long-acting intramuscular cabotegravir and rilpivirinein adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial. The Lancet (2017).

3]Pilar Mendoza etal. Combination therapy with anti-HIV-1 antibodies maintains viral suppression.Nature(2018).

4]YotamBar-On et al.Safety and antiviral activity of combination HIV -1 broadly neutralizingantibodies in viremic individuals. Nature Medicine(2018).

5]Rémi Fromentin et al.PD-1 blockadepotentiates HIV latency reversal ex vivo in CD4+T cellsfromART-suppressed individuals. Nature Communications (2019

6]A Guihot et al.Drastic decrease of the HIV reservoir in a patient treated with nivolumab forlung cancer. Annals of Oncology (2017).

7]Hsin-Kai Liao et Al. Use of the CRISPR/Cas9 system as an intracellular defense against HIV-1 infection in humancells. Nature Communications (2015).

8]ChaoranYinet al.InVivo Excision of HIV-1 Provirus by saCas9 and Multiplex Single-GuideRNAs in Animal Models. Molecular Therapy (2017).

References:

1#Secondpatient free of HIV after stem-cell therapy

2 #Newresearch shows promise for immunotherapy as HIV treatment

3#Monthly HIV injectioncould free patients from gruelling drug regimen

4# China's first anti-AIDS drug Aiken listed in China

5#FDA approves the HIV treatment drug Trogarzo, which is injected every 14 days

6#同登Nature.Nature Medicine! New anti-AIDS results, positive early clinical data

7#What is the second AIDS healer in the world?

8# Top science magazines exploded!The second case of HIV "cure" in the world has emerged

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