Combination antiretroviral therapy (ART) to treat human immunodeficiency virus (HIV) infection has proven remarkably successful – for those who can access and afford it – yet HIV infection persists indefinitely in a reservoir of cells, despite effective ART and despite host antiviral immune responses. An HIV cure is therefore the next aspirational goal and challenge, though approaches differ in their objectives – with ‘functional cures’ aiming for durable viral control in the absence of ART, and ‘sterilizing cures’ aiming for the more difficult to realize objective of complete viral eradication. Mechanisms of HIV persistence, including viral latency, anatomical sequestration, suboptimal immune functioning, reservoir replenishment, target cell-intrinsic immune resistance, and, potentially, target cell distraction of immune effectors, likely need to be overcome in order to achieve a cure. A small fraction of people living with HIV (PLWH) naturally control infection via immune-mediated mechanisms, however, providing both sound rationale and optimism that an immunological approach to cure is possible. Herein we review up to date knowledge and emerging evidence on: the mechanisms contributing to HIV persistence, as well as potential strategies to overcome these barriers; promising immunological approaches to achieve viral control and elimination of reservoir-harboring cells, including harnessing adaptive immune responses to HIV and engineered therapies, as well as enhancers of their functions and of complementary innate immune functioning; and combination strategies that are most likely to succeed. Ultimately, a cure must be safe, effective, durable, and, eventually, scalable in order to be widely acceptable and available.

联合抗逆转录病毒疗法 (ART) 治疗人类免疫缺陷病毒 (HIV) 感染已被证明非常成功——对于那些能够获得并负担得起的人来说——然而，尽管有有效的抗逆转录病毒疗法和宿主抗病毒免疫反应，但 HIV 感染会无限期地持续存在于细胞库中。因此，HIV 治愈是下一个理想目标和挑战，尽管方法的目标不同——“功能性治愈”旨在在没有 ART 的情况下实现持久的病毒控制，而“灭菌治愈”旨在实现更难实现的完全目标病毒根除。HIV 持续存在的机制，包括病毒潜伏期、解剖隔离、次优免疫功能、水库补充、靶细胞固有免疫抗性，以及潜在的免疫效应物对靶细胞的干扰，可能需要克服才能实现治愈。然而，一小部分 HIV 感染者 (PLWH) 通过免疫介导的机制自然地控制感染，这提供了合理的理由和乐观的理由，即免疫方法治愈是可能的。在此，我们回顾了以下方面的最新知识和新出现的证据：导致 HIV 持续存在的机制，以及克服这些障碍的潜在策略；实现病毒控制和消除宿主细胞的有希望的免疫学方法，包括利用对 HIV 和工程疗法的适应性免疫反应，以及增强它们的功能和补充先天免疫功能；以及最有可能成功的组合策略。最终，治疗必须是安全、有效、持久的，并且最终，