幹細胞移植已經使七人擺脫了病毒,但研究人員表示,大多數長期介入措施仍然是一個遙遠的前景。
Diana Kwon / 2024 年 9 月 2 日 / 新聞解釋器 / Nature
在七月的一次重要的愛滋病毒會議上,科學家宣布第七個人身上的這種疾病已經被「治癒」。研究人員報告稱,德國一名 60 歲男子在接受幹細胞移植後,已脫離病毒近六年。
2008 年報導了第一個以這種方式消除人體愛滋病毒的實例。這種治療具有侵略性並會帶來風險,包括移植物抗宿主疾病(供體細胞攻擊受體自身組織的疾病)引起的長期併發症。澳洲墨爾本彼得·多爾蒂感染與免疫研究所所長、傳染病醫生莎朗·萊文(Sharon Lewin) 表示,這種手術只能在七名成功治癒的患者身上進行,因為他們都患有需要骨髓移植的癌症。 「對於一個原本健康的人來說,我們甚至不會考慮這一點」,勒溫說。「沒有人認為這是治療愛滋病毒的方法」。
HIV 的標準治療方法是抗病毒療法 (ART),該療法涉及多種藥物,通常每天服用,以防止病毒在體內複製。 ART 可以將感染者的病毒量降低到無法偵測的水平,阻止病毒在體內造成嚴重破壞,並大幅降低傳播風險。但是,對許多人來說,這樣的策略還不夠。
更長期的解決方案正在制定中。但我們距離治癒愛滋病毒或疫苗還有多遠? 《自然》雜誌採訪了專家來找出答案。
愛滋病治療取得了哪些進展?
藥物供應不可靠、抗藥性和愛滋病毒感染帶來的恥辱等問題意味著許多接受抗病毒療法的人希望得到長期解決方案。英國劍橋大學微生物學家 Ravindra Gupta 表示:「許多患者表示,他們願意冒發生不良事件甚至死亡的風險來治癒愛滋病毒」。
在大多數幹細胞移植案例中,人們接受的細胞含有阻止 CCR5 表現的突變,CCR5 是 HIV 病毒用來進入細胞的蛋白質。
儘管這種手術對大多數 HIV 感染者來說是不可能的,但它在少數患者中取得的成功促進了針對 CCR5 的基因療法的開發。針對病毒本身的基因療法也正在醞釀中。例如,透過插入產生抗體的基因來控制病毒。
其他研究途徑包括努力控制或消除潛在的愛滋病毒儲存庫,這是一群不產生病毒顆粒的愛滋病毒感染細胞。因此,這些細胞對免疫系統來說是隱藏的,但在人類停止抗反轉錄病毒療法後,它們可以重新喚醒。針對此潛在病毒庫的方法包括增強免疫反應、喚醒並攻擊休眠的愛滋病毒感染細胞或讓病毒在病毒庫中永久休眠。
Lewin 表示,大多數療法尚未通過臨床試驗的 I 期或 II 期。 「我們仍在談論早期的事情」。
然而,過去幾年,長期治療取得了進展。 2020 年和 2021 年,多個國家的監管機構批准了注射抗病毒藥物卡博特韋和利匹韋林 (cabotegravir and rilpivirine) 的組合,可以每兩個月向愛滋病毒感染者注射一次,以阻止病毒感染。 2022 年,監管機構批准了注射用的來那卡韋 (lenacapavir),每六個月才需要使用一次。
怎樣防止傳播呢?
在缺乏疫苗的情況下,暴露前預防(PrEP)一直是阻止愛滋病毒傳播的關鍵。直到最近,PrEP 僅以口服藥物的形式存在,必須每天服用才能有效。如果使用正確,口服 PrEP 可以將感染 HIV 的風險降低約 99%。
一些被批准作為長效愛滋病治療的注射抗病毒藥物也被證明可以有效預防感染。 2021 年,美國食品藥物管理局 (FDA) 批准卡博特韋 (cabotegravir) 用於預防用途。 Lenacapavi 也可能很快就作為 PrEP 藥物上市:在 7 月發表的一項研究中,研究人員報告稱,每年兩次注射 Lenacapavir 成功地預防了 2,000 多名性活躍的年輕女性和少女的 HIV 感染。相比之下,在接受口服 PrEP 的人群中,約有 2% 的人感染了病毒。
巴西聖保羅聯邦大學的傳染病醫生里卡多·迪亞茲(Ricardo Diaz)是lenacapavir臨床試驗的首席研究員,他表示注射有一些限制。例如,對皮膚的副作用可能會導致某些人停止服藥。其對男性的有效性尚未確定(針對男性的臨床試驗正在進行中)。但是,鑑於最近發表的試驗中所見的功效,來那卡韋 (lenacapavir)「可能會改變愛滋病毒流行的遊戲規則」,迪亞茲說。
疫苗研發進度如何?
喬治亞州亞特蘭大埃默里大學的免疫學家 Rama Rao Amara 表示,自 1981 年首例 HIV 感染報導以來,疫苗領域在疫苗研發方面取得了穩步進展,但仍有很長的路要走。
阿馬拉說,該領域面臨的最大挑戰之一是開發一種能夠廣泛中和多種愛滋病毒株的疫苗。最重要的是,該病毒被高度糖基化(被糖分子包裹),這一事實使得設計一種能夠突破這一屏障的抗體變得困難。
在 8 月 30 日發表在《科學免疫學》上的兩篇論文中,研究人員報告了一種免疫原,可以在獼猴體內產生有效的、廣泛中和的 HIV 病毒抗體。阿馬拉說,這些研究顯示,至少可以開始讓免疫細胞產生廣泛中和抗體的過程,他在論文中撰寫了評論。「這不是一件容易的事」。這種被稱為 GT1.1 的免疫原目前正在 I 期臨床試驗中進行測試。
「愛滋病毒不是一種容易對付的病毒」,阿瑪拉說。 「否則,我們早就有疫苗了」。
doi:https://doi.org/10.1038/d41586-024-02840-5
參考文獻:
1.貝克爾,L.-G等人。 《新英格蘭醫學》。https://doi.org/10.1056/NEJMoa2407001(2024)。
2. 尼爾森,A.N. 等人。《科學免疫學》。 9、EDM7097(2024)。
3.Caniels,T.G.等。《科學免疫學》。 9、eadk9550(2024)。4.阿馬拉,R.R.。《科學免疫學》。 9、eadq8862(2024)。
HIV: how close are we to a vaccine — or a cure?
Stem-cell transplants have freed seven people of the virus, but researchers say most long-term interventions remain a distant prospect.
Diana Kwon / 02 September 2024 / NEWS EXPLAINER / Nature
At a major HIV conference in July, scientists announced that a seventh person had been ‘cured’ of the disease. A 60-year-old man in Germany, after receiving a stem-cell transplant, has been free of the virus for almost six years, researchers reported.
The first such instance of eliminating HIV from a person in this way was reported in 2008. But stem-cell transplants, despite being highly effective at ridding people of the virus, are not a scalable strategy. The treatment is aggressive and poses risks, including long-term complications from graft-versus-host disease — a condition in which donor cells attack the recipient’s own tissues. The procedure was only possible in the seven successfully treated people because all of them had cancers that required a bone-marrow transplant, says Sharon Lewin, an infectious-diseases physician who heads the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia. “We would never even contemplate this for someone who was otherwise healthy,” Lewin says. “No one is thinking about this as a cure for HIV.”
The standard treatment for HIV is antiretroviral therapy (ART), which involves a mix of drugs, usually taken daily, that prevents the virus from replicating inside the body. ART can reduce an infected person’s viral load to an undetectable level, stopping the virus from wreaking havoc in the body and drastically reducing the risk of transmission. But, for many people, such a strategy is not enough.
Longer-term solutions are in the works. But how close are we to a cure for HIV — or a vaccine?
Nature spoke with specialists to find out.
What advances have been made in the treatment of HIV?
Problems such as unreliable supply of the medicines, drug resistance and the stigma surrounding HIV infection mean that lots of people who take ART are hoping for longer-term solutions. “Many patients say they’re willing to take the risk of adverse events and even mortality risk to be cured of HIV,” says Ravindra Gupta, a microbiologist at the University of Cambridge, UK.
In most of the stem-cell-transplant cases, the cells that people received contained a mutation that prevents the expression of CCR5, a protein that the HIV virus uses to enter cells.
Although this procedure is not possible in most people with HIV, its success in a small number of patients has led to the development of gene therapies that target CCR5. There are also gene therapies in the pipeline that target the virus itself; for example, by inserting a gene that produces antibodies that keep the virus under control.
Other avenues of investigation include efforts to control or eliminate the latent HIV reservoir, which is a pool of HIV-infected cells that do not produce viral particles. These cells are thus hidden from the immune system, but they can reawaken after a person stops ART. Methods that target this latent reservoir include boosting the immune response, waking and attacking dormant HIV-infected cells or putting the virus in reservoirs permanently to sleep.
Most of these therapies have yet to make it past phase I or II in clinical trials, according to Lewin. “We’re still talking about early days.”
There have, however, been advances in longer-term treatments in the past few years. In 2020 and 2021, regulatory agencies in several countries approved a combination of injectable antiviral drugs, cabotegravir and rilpivirine, which can be given every two months to people who have HIV to keep the virus at bay. And in 2022, regulators approved the injectable lenacapavir, which is only needed every six months.
What about preventing transmission?
In the absence of vaccines, pre-exposure prophylaxis, or PrEP, has been key to stemming the spread of HIV. Until recently, PrEP existed only in the form of oral medicines that must be taken daily to be effective. When used correctly, oral PrEP reduces the risk of contracting HIV by about 99%.
Some of the injectable antivirals approved as long-acting HIV treatments have also proved to be effective at preventing infection. In 2021, the US Food and Drug Administration (FDA) approved cabotegravir for prophylactic use. Lenacapavir might also soon be available as a PrEP drug: in a study1 published in July, researchers reported that twice-yearly shots of lenacapavir successfully prevented HIV infection in a cohort of more than 2,000 sexually active young women and adolescent girls. In comparison, among the group who received oral PrEP, about 2% contracted the virus.
Ricardo Diaz, an infectious-diseases physician at the Federal University of São Paulo in Brazil, who is a principal investigator in a clinical trial of lenacapavir, says that there are some limitations of the injection. For example, side effects on the skin can lead some people to stop taking the drug. And its effectiveness has yet to be determined in men (a clinical trial of men is ongoing). But, given the efficacy seen in the recently published trial, lenacapavir “may be a game changer for HIV epidemics”, Diaz says.
What is happening in vaccine development?
The field has made steady progress towards a vaccine since the first HIV infection was reported in 1981 — but there’s still a long way to go, says Rama Rao Amara, an immunologist at Emory University in Atlanta, Georgia.
One of the biggest challenges facing the field is developing a vaccine that can broadly neutralize the multiple strains of the HIV virus, Amara says. On top of that, the fact that the virus is heavily glycosylated — coated in sugar molecules — makes it difficult to design an antibody that can break through this barrier.
In a pair of papers published in Science Immunology on 30 August, researchers report an immunogen that can generate potent, broadly neutralizing antibodies against the HIV virus in macaques. These studies show that it’s possible to at least begin the process of engaging immune cells to produce broadly neutralizing antibodies, says Amara, who penned a commentary accompanying the papers. “That is not an easy task.” The immunogen, dubbed GT1.1, is currently being tested in a phase I clinical trial.
“HIV is not an easy virus to deal with,” Amara says. “Otherwise, we would have already had a vaccine.”
doi: https://doi.org/10.1038/d41586-024-02840-5
References
- Bekker, L.-G. et al. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2407001 (2024).
- Nelson, A. N. et al. Sci. Immunol. 9, eadm7097 (2024).
- Caniels, T. G. et al. Sci. Immunol. 9, eadk9550 (2024).
- Amara, R. R. Sci. Immunol. 9, eadq8862 (2024).