Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA.
Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT 06510, USA.
Viruses. 2023 Oct 28;15(11):2171. doi: 10.3390/v15112171.
Despite remarkable progress, a cure for HIV-1 infection remains elusive. Rebound competent latent and transcriptionally active reservoir cells persevere despite antiretroviral therapy and rekindle infection due to inefficient proviral silencing. We propose a novel "block-lock-stop" approach, entailing long term durable silencing of viral expression towards an irreversible transcriptionally inactive latent provirus to achieve long term antiretroviral free control of the virus. A graded transformation of remnant HIV-1 in PLWH from persistent into silent to permanently defective proviruses is proposed, emulating and accelerating the natural path that human endogenous retroviruses (HERVs) take over millions of years. This hypothesis was based on research into delineating the mechanisms of HIV-1 latency, lessons from latency reversing agents and advances of Tat inhibitors, as well as expertise in the biology of HERVs. Insights from elite controllers and the availability of advanced genome engineering technologies for the direct excision of remnant virus set the stage for a rapid path to an HIV-1 cure.
尽管取得了显著的进展，但 HIV-1 感染的治愈仍然难以实现。尽管有抗逆转录病毒疗法，但潜伏和转录活跃的储库细胞仍然存在，并且由于前病毒沉默效率低下而重新引发感染。我们提出了一种新的“阻断-锁定-停止”方法，通过长期持久地沉默病毒表达，使前病毒处于不可逆的转录非活跃潜伏状态，从而实现长期无抗逆转录病毒控制病毒。我们提出了一种从持续性到沉默性再到永久性缺陷性前病毒的 HIV-1 在 PLWH 中的分级转化，模拟并加速了人类内源性逆转录病毒（HERV）在数百万年内接管的自然过程。这一假设基于对 HIV-1 潜伏期机制的研究、潜伏逆转剂的经验以及 Tat 抑制剂的进展，以及对 HERV 生物学的专业知识。精英控制器的见解以及用于直接切除残余病毒的先进基因组工程技术的可用性为实现 HIV-1 治愈铺平了道路。
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