Despite the fact that 59% of people living with HIV (PLHIV) currently achieve viral suppression on antiretroviral therapy (ART), recent gains in controlling the global HIV/AIDS epidemic may be threatened: key HIV incidence rates are declining only modestly, the sustainability of programs to expand ART remains unclear, and the “youth bulge” in sub-Saharan Africa contributes to a growing at-risk population.1 Although much effort has been devoted to prevention interventions, these face major technical and/or implementation challenges. A complementary approach is a safe, effective, and durable intervention that completely eliminates HIV infection (“eradication”) or that suppresses viremia in the absence of ART (“remission”) (both of these states are referred to as an “HIV cure” herein). Though a daunting goal, the scientific basis is clear: long-term remission if not eradication has been observed in the “Berlin patient”2 as well as the “London patient”3 following transplantation of bone marrow progenitor cells lacking the viral co-receptor, CCR5; and durable remission occurs in tens of thousands of PLHIV (so-called “Elite Controllers”), some of whom (“Exceptional Elite Controllers”) may have eliminated their infections through natural immunity.4,5 Ongoing work over the past decade suggests that HIV cure might be induced by some interventions, alone or in combination, including provision of broadly neutralizing antibodies (bNAbs), generation of effective antiviral CD8+ T cell responses, and knock-out of the viral co-receptor, CCR5.6 Little is known, however, about the nature and vulnerabilities of the rebound-competent viral reservoir that persists despite ART and about the immunologic control of virus in the absence of ART; today’s “best bets,” in other words, must still be viewed as long shots. Initiated by the Bill & Melinda Gates Foundation in 2019, the HIV Frontiers Program aims to move work on HIV cure towards interventions that will ultimately be available to all, most especially those in resource-limited parts of the world where the prevalence of disease is high (Figure 1). It starts with the premise that the journey will be long (15-25 years) and that it will ultimately yield a “single-shot cure,” i.e., a product that is delivered percutaneously (“in vivo”) in a single encounter, safely and effectively modifying selected cells in the body so that viral replication and spread are suppressed and re-infection blocked. This aspirational goal is likely to be realized through a series of progressive interventions that move from combination therapies provided over a longer duration of time to those in which cells are modified outside of the body (“ex vivo”) prior to re-infusion.7 The work will build on current knowledge to advance through a series of technical and practical hurdles while also gathering new knowledge to best design a curative intervention for HIV and to determine whether and how it might be used. To get to the point of having a “single-shot cure” for HIV in hand, two interlocking areas of focus are being pursued: Current Best Bets: To minimize the expected time to impact, investments are being made in all of the necessary elements of a “single-shot” HIV cure in parallel. As a critical enabler, the Program is leveraging the considerable interest and resources in biotech/pharma companies that are now developing ex vivo genetic and cell-based interventions; uniquely amongst ongoing efforts, it intends to shift the emphasis of such interventions to delivery in vivo, an approach that is much more likely to benefit those in resource-limited parts of the world. Early forms of the “single-shot” cure would tap current “best bets” (i.e., administration of two or more bNAbs, induction of a durable T cell response against HIV, and CCR5 knock-out), quickly pivoting to others should they arise, and asking the questions: can these interventions be delivered efficiently and safely to appropriate cell populations in vivo; if so, can they be associated with methods to detect their failure; and, importantly, is there a viable pathway for product development and distribution in sub-Saharan Africa? Incremental steps are being taken to maximize the likelihood of success, with development and validation of novel approaches for targeting and editing selected populations of cells (e.g., hematopoietic stem cells, CD4+ T stem central memory cells, and B cells) in vivo. At the outset, this work is taking advantage of genetic “cures” for sickle cell disease that are now in hand, with early results indicating that substantial clinical benefit can be obtained with even incomplete correction of the hemoglobin S genotype (either by editing the hemoglobin S allele or by upregulating hemoglobin F) in hematopoietic stem cells ex vivo.8 Successful efforts to modify hematopoietic stem cells in vivo to result in similar corrections might form a pathway to the in vivo introduction of modifications aimed at HIV cure. If successful, the ultimate product will be an inexpensive composition that is easily and safely delivered, and designed to effect a durable HIV cure for all; en route, interventions providing benefit for those with sickle cell disease (as well as other hemoglobinopathies) should predictably arise. The HIV Reservoirs Consortium: In this program, a consortium of academic labs has been established to define the biology of the rebound-competent reservoir of HIV in vivo and, in particular, to discover circulating non-viral biomarkers that can be used to monitor it over time. A strategically focused, multidisciplinary team effort is carrying out studies in PLHIV in resource-limited parts of the world as well as in non-human primate models that recapitulate relevant aspects of human HIV infection and in which the reservoir can be systematically perturbed with interventions that could not be used in humans. Using state-of-the-art assays, it is hoped that circulating non-viral biomarkers for the rebound-competent reservoir will be discovered in the non-human primate, cross-validated in the human, and assessed for their ability to define the size and quality of the rebound-competent reservoir while on ART and the time to viral rebound once ART is discontinued. Of note, the HIV Frontiers Program pre-supposes the will to assume and to share significant risk. Substantial new financial resources and a sustained commitment will be required to pursue the multiple components of a “single-shot” HIV cure in parallel and to simultaneously launch the HIV Reservoirs Consortium. Such resources and commitment will not arise from a single source; rather, partnerships must be formed and strategic priorities set. This review will outline some of the steps that are being taken to reach these goals.

中文翻译：

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将 HIV 疾病的基因疗法带到世界资源有限的地区

尽管 59% 的艾滋病毒感染者 (PLHIV) 目前通过抗逆转录病毒疗法 (ART) 实现了病毒抑制，但最近在控制全球艾滋病毒/艾滋病流行方面取得的成果可能会受到威胁：关键的艾滋病毒发病率仅略有下降，可持续性扩大 ART 的计划尚不明确，撒哈拉以南非洲的“青年膨胀”导致高危人群不断增加。1 尽管在预防干预方面付出了很多努力，但这些都面临着重大的技术和/或实施挑战。补充方法是一种安全、有效和持久的干预措施，可以完全消除 HIV 感染（“根除”）或在没有 ART 的情况下抑制病毒血症（“缓解”）（这两种状态都称为“HIV 治愈”在此处）。虽然这是一个艰巨的目标，但科学依据是明确的：在移植缺乏病毒共受体 CCR5 的骨髓祖细胞后，在“柏林患者”2 和“伦敦患者”3 中观察到即使没有根除也有长期缓解；数以万计的 PLHIV（所谓的“精英控制者”）出现持久缓解，其中一些人（“杰出的精英控制者”）可能已经通过自然免疫消除了感染。 4,5 过去十年正在进行的工作表明HIV 治愈可能通过一些单独或组合的干预措施诱导，包括提供广泛中和抗体 (bNAb)、产生有效的抗病毒 CD8+ T 细胞反应，以及敲除病毒共受体 CCR5.6 鲜为人知， 然而，关于在 ART 下仍然存在的具有反弹能力的病毒库的性质和脆弱性，以及在没有 ART 的情况下病毒的免疫控制；换句话说，今天的“最佳赌注”仍被视为机会渺茫。由比尔和梅琳达·盖茨基金会于 2019 年发起的艾滋病毒前沿计划旨在将艾滋病毒治愈工作转向最终提供给所有人的干预措施，尤其是那些在世界上资源有限、疾病流行率很高的地区。 （图1）。它的前提是旅程将很长（15-25 年），并且最终将产生“单次治疗”，即在一次接触中经皮（“体内”）递送的产品，安全有效地修改体内选定的细胞，从而抑制病毒复制和传播并阻止再次感染。这一理想目标可能会通过一系列渐进的干预措施实现，这些干预措施从长期提供的联合疗法转变为在重新输注之前在体外（“离体”）对细胞进行修饰的疗法。 7这项工作将建立在现有知识的基础上，以克服一系列技术和实践障碍，同时收集新知识以最好地设计 HIV 治疗干预措施，并确定是否以及如何使用它。为了达到手头有 HIV 的“一次性治愈”的地步，正在追求两个相互关联的重点领域： 当前最佳选择：为了尽量减少预期的影响时间，正在同时对“一次性”艾滋病毒治疗的所有必要要素进行投资。作为一个关键的推动者，该计划正在利用生物技术/制药公司的巨大兴趣和资源，这些公司现在正在开发离体遗传和基于细胞的干预措施；在正在进行的努力中，它的独特之处在于，它打算将此类干预措施的重点转移到体内递送，这种方法更有可能使世界上资源有限地区的人们受益。“单次”治疗的早期形式将利用当前的“最佳选择”（即，施用两种或多种 bNAb，诱导针对 HIV 的持久 T 细胞反应，以及 CCR5 敲除），如果他们应该迅速转向其他人出现，并提出问题：这些干预措施能否在体内有效、安全地传递给适当的细胞群；如果是这样，它们是否可以与检测其故障的方法相关联？而且，重要的是，在撒哈拉以南非洲地区是否存在可行的产品开发和分销途径？正在采取渐进措施以最大限度地提高成功的可能性，开发和验证用于在体内靶向和编辑选定细胞群（例如，造血干细胞、CD4+ T 干中央记忆细胞和 B 细胞）的新方法。一开始，这项工作利用了现有的镰状细胞病的遗传“治疗方法”，早期结果表明，即使不完全校正血红蛋白 S 基因型（通过编辑血红蛋白S 等位基因或通过上调离体造血干细胞中的血红蛋白 F)。8 成功地在体内修饰造血干细胞以产生类似的修正可能会形成一条途径，以在体内引入旨在治愈 HIV 的修饰。如果成功，最终的产品将是一种廉价的组合物，可以轻松安全地输送，并旨在为所有人实现持久的 HIV 治愈；在此过程中，应该可以预见地出现为患有镰状细胞病（以及其他血红蛋白病）的人带来益处的干预措施。The HIV Reservoirs Consortium：在这个项目中，建立了一个学术实验室联盟来定义体内 HIV 反弹能力储存库的生物学，特别是发现可用于监测它的循环非病毒生物标志物随着时间的推移。一个战略重点，多学科团队正在世界资源有限的地区以及非人类灵长类动物模型中开展 PLHIV 研究，这些模型概括了人类 HIV 感染的相关方面，并且可以通过无法使用的干预措施系统地扰乱病毒库在人类中。使用最先进的检测方法，希望在非人类灵长类动物中发现具有反弹能力的水库的循环非病毒生物标志物，在人类中进行交叉验证，并评估它们定义病毒的能力抗逆转录病毒治疗期间具有反弹能力的病毒库的大小和质量，以及停止抗逆转录病毒治疗后病毒反弹的时间。值得注意的是，HIV 前沿项目预设了承担和分担重大风险的意愿。将需要大量新的财政资源和持续的承诺，以同时追求“一次性”艾滋病毒治疗的多个组成部分，并同时启动艾滋病毒储存库联盟。此类资源和承诺不会来自单一来源；相反，必须建立伙伴关系并确定战略优先事项。本次审查将概述为实现这些目标而采取的一些步骤。