少數人是如何治癒愛滋病毒的
科學家們通過接受血癌治療，治癒了少數愛滋病毒感染者。但這是否會帶來更廣泛的治療？
資料來源：BENJAMIN RYAN / 2022 年 10 月 5 日/ NOVA NEXT / 財團法人台灣紅絲帶基金會編譯
從受感染的 H9 T 細胞的質膜複製的 HIV-1 病毒顆粒（橙色）的透射電子顯微照片。來源：NIAID，Flickr
在過去的一年裡，兩個新的愛滋病毒治癒者的消息登上了頭條，引發了人們對這些科學奇蹟可能預示著四年抗擊病毒的充滿希望的討論。
對於在 HIV 治癒領域工作的研究人員來說，這些案例是鼓舞人心的，因為它們證明實際上有可能從體內根除這種極其複雜的病毒。
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相關的訊息
第二名患者已進入愛滋病毒長期緩解期
HIV 蛋白的「社交網絡」揭示了為什麼一些患者比其他患者更好地控制感染
在美國終結愛滋病毒
也就是說，這種治療方法的結果是毒性太大，只能對少數人進行嘗試。因此，儘管它們提供了通向成功的科學路線圖，但它們並不一定會使研究人員的工作變得更容易，因為他們致力於開發替代方案：安全、有效且至關重要的是，可擴展的治療 HIV 的療法。
「追踪 HIV 一直是個難題」，紐約市威爾康奈爾醫學中心的傳染病專家、最近 HIV 治癒案例研究之一的合著者 Marshall Glesby 說。「但在我們了解病毒在體內的隱藏位置以及從這些位置清除病毒的潛在方法方面，我們正在取得漸進的進展」。
HIV治癒研究領域還很年輕。如果不是因為第一次成功的治癒——它為科學家們充當了催化劑和指路明燈，它可能永遠不會像近年來那樣如氣球般膨脹擴展。
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變革性的成功
在 1990 年代末和 2000 年代初，愛滋病毒研究機構將大部分精力和資源集中在病毒的治療和預防上。實際上治癒愛滋病毒被普遍認為是一個遙遠的夢想，只有一小部分研究人員追求這樣的目標。
然後，在 2008 年，德國科學家宣布了第一例最終被視為成功治癒該病毒的病例。根據 HIV 非營利組織 AVAC 的數據，這一概念驗證點燃了該領域並推動金融投資飆升——到 2020 年非製藥行業資金達到 3.37 億美元。
臨床醫生利用他也被診斷出患有急性髓性白血病 (acute myeloid leukemia , AML) 的事實，治癒了居住在柏林的美國人蒂莫西·雷·布朗 (Timothy Ray Brown) 的 HIV。這使布朗成為幹細胞（骨髓）移植治療他的血癌的候選人。
布朗的治療團隊依賴於在北歐血統的人群中發現的一種罕見的遺傳異常。被稱為 CCR5-delta32 突變，它會導致免疫細胞在其表面缺乏某種稱為 CCR5 的輔助受體。這是一個鉤子，愛滋病毒通常會抓住這個鉤子，開始感染免疫細胞並劫持其機器製造新的病毒副本。
臨床醫生發現了一位幹細胞供體，他不僅與布朗基因匹配，而且還具有 CCR5-delta32 突變。首先，他們用全劑量化療和全身放射治療破壞了布朗的免疫系統。然後他們透過幹細胞移植有效地為他提供了捐贈者的免疫系統。透過確保他體內任何殘留的病毒都無法感染他的新免疫細胞，這治癒了他的 HIV。
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在美國終結愛滋病毒（2022 年）
從那以後的幾年裡，這種方法的變化已經在另外四個人身上產生了治癒或可能治癒的效果。這些案例為研究人員提供了越來越多的確定性，即有可能實現最終目標：一種消毒療法，在這種方法中，身體已經擺脫了能夠產生可行的新副本的病毒的每一個副本。
俄勒岡健康與基因治療研究所副所長路易斯·皮克說：「如果你完全取代免疫系統，即使是據稱不易感染的免疫系統，也不能治癒感染」。理科大學。「HIV 有可能隱藏在非免疫細胞中，如內皮細胞，但仍能找到感染目標」。
但皮克說，迄今為止已經治癒或可能治癒的一小部分人「顯示情況並非如此」。
然而，這些成功並沒有為全世界大約 3,800 萬愛滋病毒感染者中的少數人打開治癒愛滋病毒的大門。至關重要的是，向沒有資格進行幹細胞移植治療血癌或其他健康狀況的任何人提供這種危險和有毒的治療是不道德的。
布朗，其中之一，幾乎死於他的治療。許多重複他的案例的努力都失敗了。
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為什麼愛滋病這麼難治癒？
1996 年，針對 HIV 的高效療法上市，將曾經的死刑判決轉變為可控制的健康狀況。今天，這種療法是一種稱為抗反轉錄病毒藥物的組合，非常安全、可耐受和有效，它已將接受者的預期壽命延長至接近正常水平。但是，儘管這些藥物可以將病毒複製抑製到標準測試無法檢測到的程度，但它們無法從體內根除 HIV。
擋路的是所謂的愛滋病毒貯藏窩。
這個病毒貯藏窩主要由進入靜息或潛伏狀態的長壽免疫細胞所組成。抗反轉錄病毒藥物只針對積極產生病毒新拷貝的細胞。因此，當 HIV 感染了處於非複制狀態的細胞時，病毒仍處於這些藥物的雷達之下。停止治療，在任何時候，這些複製自己的細胞中的任何一個都可以重新啟動它們的引擎，並用 HIV 重新填充人體。
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經由學習更多提供支持
這種現象就是為什麼愛滋病病毒感染者通常會在停止抗反轉錄病毒藥物的幾週內經歷病毒反彈。這就是為什麼鑑於這種病毒複製對身體造成的傷害，愛滋病毒感染者必須無限期地繼續接受抗病毒治療，以減輕感染的有害影響。
「一個關鍵的新進展是發現那些攜帶病毒的細胞似乎對死亡有抵抗力，這是癌細胞的一個問題」，加州大學舊金山分校的醫學教授、愛滋病毒治癒研究員史蒂文迪克斯談到病毒貯藏窩時說. 「我們將利用新的癌症療法來瞄準這些有彈性、難以殺死的細胞」。
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後續行動
布朗獨自站在他的基座上已十多年。
然後，在西雅圖舉行的 2019 年反轉錄病毒和機會性感染會議 (CROI) 上，研究人員宣布了兩項關於接受與布朗類似治療的血癌和 HIV 男性的新案例研究。這些被稱為杜塞多夫和倫敦患者的男性分別接受了霍奇金淋巴瘤和 AML 治療。到會議召開時，兩人都已長時間停止抗反轉錄病毒治療，但沒有出現病毒反彈。
直到今天，兩人都沒有經歷過病毒性反彈——這導致倫敦和杜塞多夫案例研究的作者最近斷言他們分別「肯定」和「幾乎肯定」治癒。
2022 年 2 月，一組研究人員在 CROI 報告，虛擬地舉行了女性 HIV 治癒的首例可能病例。她為白血病所接受的治療代表了一項重要的科學進步。
這種治療血癌的尖端方法被稱為單倍體臍帶移植，旨在彌補在幹細胞供體中尋找密切遺傳匹配的困難——傳統上需要這種方法為幹細胞移植提供最佳機會以好好工作。在試圖治癒 HIV 時，這種努力變得更具挑戰性，因為 CCR5-delta32 突變非常罕見。
這位美國婦女接受了嬰兒的臍帶血移植，該嬰兒具有基因突變，緊跟著再移植了成人的幹細胞，而後者並沒有基因突變。雖然每個捐贈者只是部分匹配，但兩次移植的組合旨在彌補這種不太理想的情況。結果是一種新的抗愛滋病毒之免疫系統的成功開花。
該女性案例研究的作者，包括威爾康奈爾大學的 Marshall Glesby，估計這種新方法可以將愛滋病毒治癒治療的候選人數量擴大到每年約 50 人。
用於治療 HIV 感染的多種抗反轉錄病毒藥物。圖片來源：NIAID，Flickr
7 月，在蒙特婁舉行的國際愛滋病大會上，研究人員宣布了第五個可能治癒 HIV 的人的病例。這位美國人於 1988 年被診斷出感染了這種病毒，三年前他進行幹細胞移植時已經 63 歲，他是透過這種治療取得潛在成功的最年長的人，也是感染該病毒時間最長的人。由於他的年齡，他接受了降低強度的化療來治療他的 AML。令人欣慰的是，他仍然戰勝了癌症和病毒。
此人案例研究的主要作者、加利福尼亞州杜阿爾特市希望之城傳染病臨床副教授 Jana K. Dickter 說，這些案例為研究人員提供了指導。「如果我們能夠成功地為 HIV 感染者改造 T 細胞中的 CCR5 受體」，她說，「那麼我們就有可能治癒一個人的 HIV 感染」。
科學家們還知道有兩名女性的免疫系統似乎已經治癒了她們的 HIV。兩人都屬於大約每 200 名愛滋病毒感染者中的一名，被稱為精英控制者，他們的免疫系統能夠在不進行抗反轉錄病毒治療的情況下將病毒複製抑制到低水平。
研究人員認為，這些女性的免疫系統能夠優先消除感染病毒 DNA 的免疫細胞，這些病毒 DNA 能夠產生可行的新病毒，最終成功根除每一個這樣的副本。
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尋找聖杯
隨著他們尋求比幹細胞移植方法更安全、更廣泛適用的治療選擇，HIV 治癒研究人員正在尋求各種途徑。
一些研究人員正在開發基因治療，例如，他們試圖編輯個體自身的免疫細胞，使其缺乏 CCR5 輔助受體。
「讓我特別興奮並且我們和其他人正在研究的科學是使這種治療成為一種不依賴移植中心，並且最終可以在門診環境中進行的體內可交付療法」，西雅圖弗雷德哈欽森癌症中心幹細胞和基因治療計畫主任Hans-Peter Kiem說道。
然後是所謂的「震驚和殺死」方法，其中藥物用於將病毒從儲存窩中沖洗出來，然後使用其他治療方法殺死受感染的細胞。相反，「阻塞和鎖定」則試圖將儲存細胞永久凍結在潛伏狀態。研究人員還在開發治療性疫苗，以增強對病毒的免疫反應。
「進展將是漸進的和緩慢的」，皮克預測道，「除非有來自左外野（左側領域）的發現——一個不可預測的進展，徹底改變了該領域。我確實認為它會發生。我個人的目標是成為一名出色的左外野手」。該報告得到了全球健康報告中心的支持。
How a select few people have been cured of HIV
Scientists have cured a handful of people of HIV by piggybacking on treatments they received for blood cancer. But does that bring a widespread cure any closer?
BENJAMIN RYAN / WEDNESDAY, OCTOBER 5, 2022 / NOVA NEXT
A transmission electron micrograph of HIV-1 virus particles (orange) replicating from the plasma membrane of an infected H9 T cell. Credit: NIAID, Flickr
Over the past year, news of two new people cured of HIV grabbed headlines, stirring hopeful talk of what these scientific wonders might portend for the four-decade fight against the virus.
To researchers working in the HIV cure arena, these cases are inspiring because they prove it is in fact possible to eradicate this extraordinarily complex virus from the body.
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Ending HIV in America
That said, such cures are the result of treatments too toxic to attempt on all but a select few. So while they provide a scientific roadmap toward success, they do not necessarily make researchers’ job any easier as they work to develop alternatives: safe, effective and, crucially, scalable therapies to cure HIV.
“HIV has been a tough nut to track,” says Marshall Glesby, an infectious disease specialist at Weill Cornell Medicine in New York City and a coauthor of one of the recent HIV cure case studies. “But there is incremental progress being made in terms of our understanding of where the virus hides within the body and potential ways to purge it from those sites.”
The HIV cure research field is yet quite young. And it likely never would have ballooned as it has in recent years were it not for the very first successful cure—one that served as a catalyst and guiding light for scientists.
A transformative success
During the late 1990s and early 2000s, the HIV research establishment focused the lion’s share of its energy and resources on treatment and prevention of the virus. Actually curing HIV was generally regarded as a distant dream, with only a small set of researchers pursuing such a goal.
Then, in 2008, German scientists announced the first case of what would ultimately be deemed a successful cure of the virus. This proof of concept ignited the field and sent financial investment soaring—to $337 million in non–pharmaceutical industry funding in 2020, according to the HIV nonprofit AVAC.
Clinicians were able to cure HIV in an American man living in Berlin named Timothy Ray Brown, by exploiting the fact that he had also been diagnosed with acute myeloid leukemia, or AML. This made Brown a candidate for a stem cell (bone marrow) transplant to treat his blood cancer.
Brown’s treatment team relied on the existence of a rare genetic abnormality found among people with northern European ancestry. Known as the CCR5-delta32 mutation, it gives rise to immune cells lacking a certain coreceptor called CCR5 on their surface. This is a hook to which HIV typically latches to begin the process of infecting an immune cell and hijacking its machinery to manufacture new copies of the virus.
The clinicians found a stem cell donor who was not only a good genetic match for Brown, but who also had the CCR5-delta32 mutation. First they destroyed Brown’s immune system with full-dose chemotherapy and full-body radiation. Then they effectively gave him the donor’s immune system through the stem cell transplant. This cured his HIV by ensuring that any remaining virus in his body was incapable of infecting his new immune cells.
Ending HIV in America (2022)
Variations of this method have yielded cures, or likely cures, in four other people during the years since. These cases provide researchers with increasing certainty that it is possible to achieve the ultimate goal: a sterilizing cure, in which the body has been rid of every last copy of virus capable of producing viable new copies of itself.
“It was not a given that if you completely replace the immune system, even with a purportedly non-susceptible immune system, that you would cure infection,” says Louis Picker, associate director of the Vaccine and Gene Therapy Institute at the Oregon Health & Science University. “It was possible that HIV could be hiding in non-immune cells, like endothelial cells, and still find targets to infect.”
But the small cohort of people who have been cured or likely cured to date, Picker says, “show that’s not the case.”
Nevertheless, these successes have not opened the door to a cure for HIV available to much more than a few of the estimated 38 million people living with the virus worldwide. Critically, it is unethical to provide such a dangerous and toxic treatment to anyone who does not already qualify for a stem cell transplant to treat blood cancer or another health condition.
Brown, for one, nearly died from his treatment. And a number of efforts to repeat his case have failed.
Why is HIV so hard to cure?
Highly effective treatment for HIV hit the market in 1996, transforming what was once a death sentence into a manageable health condition. Today, the therapy, a combination of drugs called antiretrovirals, is so safe, tolerable and effective, that it has extended recipients’ life expectancy to near normal. But despite the fact that these medications can inhibit viral replication to such a degree that it’s undetectable by standard tests, they cannot eradicate HIV from the body.
Standing in the way is what’s known as the HIV reservoir.
This viral reservoir is composed in large part of long-lived immune cells that enter a resting, or latent, state. Antiretrovirals only target cells that are actively producing new copies of the virus. So when HIV has infected a cell that is in a non-replicating state, the virus remains under the radar of these medications. Stop the treatment, and at any moment, any of these cells, which clone themselves, can restart their engines and repopulate the body with HIV.
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This phenomenon is why people with HIV typically experience a viral rebound within a few weeks of stopping their antiretrovirals. And it is the reason why, given the harm such viral replication causes the body, those living with HIV must remain on treatment for the virus indefinitely to mitigate the deleterious impacts of the infection.
“A key new advance is the finding that those cells which harbor the virus seem resistant to dying, a problem with cancer cells,” HIV cure researcher Steven Deeks, a professor of medicine at University of California, San Francisco, says of the viral reservoir. “We will be leveraging new cancer therapies aimed at targeting these resilient, hard-to-kill cells.”
Follow-up acts
Brown stood alone on his pedestal for over a decade.
Then, at the 2019 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, researchers announced two new case studies of men with blood cancer and HIV who had received treatments similar to Brown’s. The men, known as the Düsseldorf and London patients, were treated for Hodgkin lymphoma and AML, respectively. By the time of the conference, both had spent extended periods off of antiretroviral treatment without a viral rebound.
To this day, neither man has experienced a viral rebound—leading the authors of the London and Düsseldorf case studies recently to assert that they are “definitely” and “almost definitely” cured, respectively.
In February 2022, a team of researchers reported at CROI, held virtually, the first possible case of an HIV cure in a woman. The treatment she received for her leukemia represented an important scientific advance.
Called a haplo-cord transplant, this cutting-edge approach to treating blood cancer was developed to compensate for the difficulty of finding a close genetic match in the stem cell donor–which is traditionally needed to provide the best chance that the stem cell transplant will work properly. Such an effort is made even more challenging when attempting to cure HIV, because the CCR5-delta32 mutation is so rare.
The American woman received a transplant of umbilical cord blood from a baby, who had the genetic mutation, followed by a transplant of stem cells from an adult, who did not. While each donor was only a partial match, the combination of the two transplants was meant to compensate for this less-than-ideal scenario. The result was the successful blooming of a new, HIV-resistant immune system.
The authors of the woman’s case study, including Weill Cornell’s Marshall Glesby, estimate that this new method could expand the number of candidates for HIV cure treatment to about 50 per year.
A variety of antiretroviral drugs used to treat HIV infection. Image Credit: NIAID, Flickr
In July, at the International AIDS Conference in Montreal, researchers announced the case of a fifth person possibly cured of HIV. Diagnosed with the virus in 1988 and 63 years old at the time of his stem cell transplant three years ago, the American man is the oldest to have achieved potential success with such a treatment and the one living with the virus for the longest. Because of his age, he received reduced intensity chemotherapy to treat his AML. Promisingly, he still beat both the cancer and the virus.
The lead author of this man’s case study, Jana K. Dickter, an associate clinical professor of infectious disease at City of Hope in Duarte, California, says that such cases provide a guide for researchers. “If we are able to successfully modify the CCR5 receptors from T cells for people living with HIV,” she says, “then there is a possibility we can cure a person from their HIV infection.”
Scientists also know of two women whose own immune systems, in an extraordinary feat, appear to have cured them of HIV. Both are among the approximately 1 in 200 people with HIV, known as elite controllers, whose immune systems are able to suppress replication of the virus to low levels without antiretroviral treatment.
Researchers believe that these women’s immune systems managed to preferentially eliminate immune cells infected with viral DNA capable of producing viable new virus, ultimately succeeding in eradicating every last such copy.
The search for the holy grail
As they seek safer and more broadly applicable therapeutic options than the stem cell transplant approach, HIV cure researchers are pursuing a variety of avenues.
Some investigators are developing genetic treatments in which, for example, they attempt to edit an individual’s own immune cells to make them lack the CCR5 coreceptor.
“The science that I am particularly excited about and that we and others are working on is to make this treatment as an in vivo deliverable therapy that would not rely on transplant centers and could ultimately be given in an outpatient setting,” says Hans-Peter Kiem, director of the stem cell and gene therapy program at the Fred Hutchinson Cancer Center in Seattle.
Then there is what’s known as the “shock and kill” method, in which drugs are used to flush the virus from the reservoir and other treatments are then used to kill off the infected cells. Conversely, “block and lock” attempts to freeze the reservoir cells in a latent state for good. Researchers are also developing therapeutic vaccines that would augment the immune response to the virus.
“Progress will be incremental and slow,” Picker predicts, “unless there is a discovery from left field—an unpredictable advance that revolutionizes the field. I do think it will happen. My personal goal is to be a very good left fielder.”
This reporting was supported by the Global Health Reporting Center.