Centre for Microbiology Research-Kenya medical Research Institute, P.O Box 54840-00200, Nairobi, Kenya.
Centre for Virology Research-Kenya medical Research Institute, P.O Box 54840-00200, Nairobi, Kenya.
Curr HIV Res. 2021;19(1):14-26. doi: 10.2174/1570162X18999200819172009.
During the past 35 years, highly effective ART has saved the lives of millions of people worldwide by suppressing viruses to undetectable levels. However, this does not translate to the absence of viruses in the body as HIV persists in latent reservoirs. Indeed, rebounded HIV has been recently observed in the Mississippi and California infants previously thought to have been cured. Hence, much remains to be learned about HIV latency, and the search for the best strategy to eliminate the reservoir is the direction current research is taking. A systems-level approach that fully recapitulates the dynamics and complexity of HIV-1 latency In vivo and is applicable in human therapy is prudent for HIV eradication to be more feasible.
The main barriers preventing the cure of HIV with antiretroviral therapy have been identified, progress has been made in the understanding of the therapeutic targets to which potentially eradicating drugs could be directed, integrative strategies have been proposed, and clinical trials with various alternatives are underway. The aim of this review is to provide an update on the main advances in HIV eradication, with particular emphasis on the obstacles and the different strategies proposed. The core challenges of each strategy are highlighted and the most promising strategy and new research avenues in HIV eradication strategies are proposed.
A systematic literature search of all English-language articles published between 2015 and 2019, was conducted using MEDLINE (PubMed) and Google scholar. Where available, medical subject headings (MeSH) were used as search terms and included: HIV, HIV latency, HIV reservoir, latency reactivation, and HIV cure. Additional search terms consisted of suppression, persistence, establishment, generation, and formation. A total of 250 articles were found using the above search terms. Out of these, 89 relevant articles related to HIV-1 latency establishment and eradication strategies were collected and reviewed, with no limitation of study design. Additional studies (commonly referenced and/or older and more recent articles of significance) were selected from bibliographies and references listed in the primary resources.
In general, when exploring the literature, there are four main strategies heavily researched that provide promising strategies to the elimination of latent HIV: Haematopoietic Stem-Cell Transplantation, Shock and Kill Strategy, Gene-specific transcriptional activation using RNA-guided CRISPR-Cas9 system, and Block and Lock strategy. Most of the studies of these strategies are applicable in vitro, leaving many questions about the extent to which, or if any, these strategies are applicable to complex picture In vivo. However, the success of these strategies at least shows, in part, that HIV-1 can be cured, though some strategies are too invasive and expensive to become a standard of care for all HIV-infected patients.
Recent advances hold promise for the ultimate cure of HIV infection. A systems-level approach that fully recapitulates the dynamics and complexity of HIV-1 latency In vivo and applicable in human therapy is prudent for HIV eradication to be more feasible. Future studies aimed at achieving a prolonged HIV remission state are more likely to be successful if they focus on a combination strategy, including the block and kill, and stem cell approaches. These strategies propose a functional cure with minimal toxicity for patients. It is believed that the cure of HIV infection will be attained in the short term if a strategy based on purging the reservoirs is complemented with an aggressive HAART strategy.
在过去的 35 年中，高效的抗逆转录病毒疗法（ART）通过将病毒抑制到无法检测的水平，挽救了全球数百万人的生命。然而，这并不意味着病毒在体内不存在，因为 HIV 仍然存在于潜伏的储库中。事实上，最近在密西西比州和加利福尼亚州的婴儿中观察到了反弹的 HIV，这些婴儿以前被认为已经治愈。因此，人们对 HIV 潜伏期还有很多需要了解，寻找消除储库的最佳策略是当前研究的方向。一种能够充分再现 HIV-1 潜伏期体内动力学和复杂性的系统水平方法，并且适用于人体治疗，对于实现 HIV 根除更为可行。
确定了阻止 HIV 通过抗逆转录病毒疗法治愈的主要障碍，加深了对潜在根除药物靶向的治疗靶点的理解，提出了综合策略，并正在进行各种替代方案的临床试验。本综述的目的是提供 HIV 根除方面的主要进展更新，特别强调障碍和提出的不同策略。强调了每个策略的核心挑战，并提出了 HIV 根除策略中最有前途的策略和新的研究途径。
对 2015 年至 2019 年间发表的所有英文文章进行了系统的文献检索，使用 MEDLINE（PubMed）和 Google Scholar 进行了检索。如果有可用的医学主题词（MeSH），则将其用作搜索词，并包括：HIV、HIV 潜伏期、HIV 储库、潜伏期再激活和 HIV 治愈。其他搜索词包括抑制、持续存在、建立、产生和形成。使用上述搜索词共找到 250 篇文章。其中，有 89 篇与 HIV-1 潜伏期建立和根除策略相关的文章被收集并进行了综述，对研究设计没有任何限制。从主要资源的参考文献和列出的参考文献中选择了其他研究（通常引用的和更旧的和更重要的文章）。
一般来说，在探索文献时，有四种主要策略受到了广泛研究，为消除潜伏性 HIV 提供了有希望的策略：造血干细胞移植、休克和杀伤策略、使用 RNA 指导的 CRISPR-Cas9 系统进行基因特异性转录激活，以及阻断和锁定策略。这些策略的大多数研究都可在体外进行，这就提出了一个问题，即在多大程度上或是否可以将这些策略应用于体内复杂的情况。然而，这些策略的成功至少表明，HIV-1 可以被治愈，尽管一些策略过于侵入性和昂贵，无法成为所有 HIV 感染患者的标准治疗方法。
最近的进展为 HIV 感染的最终治愈带来了希望。一种能够充分再现 HIV-1 潜伏期体内动力学和复杂性的系统水平方法，并且适用于人体治疗，对于实现 HIV 根除更为可行。如果未来的研究专注于联合策略，包括阻断和杀伤以及干细胞方法，以实现长期的 HIV 缓解状态，那么成功的可能性更大。这些策略为患者提供了一种具有最小毒性的功能性治愈。如果一种基于清除储库的策略与积极的高效抗逆转录病毒治疗（HAART）策略相补充，那么人们相信 HIV 感染的治愈将在短期内实现。
