Noorsaeed Somaya, AlBurtamani Nawal, Rokan Ahmed, Fassati Ariberto
Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
Division of Infection & Immunity and Institute of Immunity and Transplantation, University College London, London, United Kingdom.
PLoS Pathog. 2025 Apr 1;21(4):e1012524. doi: 10.1371/journal.ppat.1012524. eCollection 2025 Apr.
An estimated 32 million people live with HIV-1 globally. Combined antiretroviral therapy suppresses viral replication but therapy interruption results in viral rebound from a latent reservoir mainly found in memory CD4+ T cells. Treatment is therefore lifelong and not curative. Eradication of this viral reservoir requires hematopoietic stem cell transplantation from hemizygous or homozygous ΔCCR5 donors, which is not broadly applicable. Alternative cure strategies include the pharmacological reactivation of latently infected cells to promote their immune-mediated clearance, or the induction of deep latency. HIV-1 latency is multifactorial and linked to the activation status of the infected CD4+ T cell. Hence to perturb latency, multiple pathways need to be simultaneously targeted without affecting CD4+ T cell function. Hsp90 has been shown to regulate HIV-1 latency, although knowledge on the pathways is limited. Because Hsp90 promotes the proper folding of numerous cellular proteins required for HIV-1 gene expression, we hypothesized that Hsp90 might be a master regulator of latency. We tested this hypothesis using a polyclonal Jurkat cell model of latency and ex-vivo latently infected primary CD4+ T cells. We found that, in the Jurkat model, Hsp90 is required for HIV-1 reactivation mediated by the T-cell receptor, phorbol esters, TNF-α, inhibition of FOXO-1, and agonists of TLR-7 and TLR-8. In primary cells, Hsp90 regulates HIV-1 gene expression induced by stimulation of the T-cell receptor or in the presence of IL-7/IL-15 or a FOXO-1 inhibitor. Chemical inhibition of Hsp90 abrogated activation of the NF-kB, NFAT and AP-1 signal transduction pathways. Within the CD4+ T cell population, CDRA45+ CCR7+ "naïve" and CD45RA- CCR7- "effector memory" cells were most sensitive to Hsp90 inhibition, which did not perturb their phenotype or activation state. Our results indicate that Hsp90 is a master regulator of HIV-1 latency that can potentially be targeted in cure strategies.
据估计，全球有3200万人感染了HIV-1。联合抗逆转录病毒疗法可抑制病毒复制，但治疗中断会导致病毒从主要存在于记忆CD4+ T细胞中的潜伏库中反弹。因此，治疗是终身的，且无法治愈。根除这种病毒库需要来自半合子或纯合子ΔCCR5供体的造血干细胞移植，但这种方法无法广泛应用。替代的治愈策略包括对潜伏感染细胞进行药理学再激活以促进其免疫介导的清除，或诱导深度潜伏。HIV-1潜伏是多因素的，与受感染CD4+ T细胞的激活状态有关。因此，要干扰潜伏，需要同时靶向多个途径而不影响CD4+ T细胞功能。虽然关于相关途径的知识有限，但已表明热休克蛋白90（Hsp90）可调节HIV-1潜伏。由于Hsp90促进HIV-1基因表达所需的众多细胞蛋白的正确折叠，我们推测Hsp90可能是潜伏的主要调节因子。我们使用潜伏的多克隆Jurkat细胞模型和体外潜伏感染的原代CD4+ T细胞来验证这一假设。我们发现，在Jurkat模型中，Hsp90是T细胞受体、佛波酯、TNF-α、FOXO-1抑制以及TLR-7和TLR-8激动剂介导的HIV-1再激活所必需的。在原代细胞中，Hsp90调节T细胞受体刺激或存在IL-7/IL-15或FOXO-1抑制剂时诱导的HIV-1基因表达。Hsp90的化学抑制消除了NF-κB、NFAT和AP-1信号转导途径的激活。在CD4+ T细胞群体中，CD45RA+ CCR7+“初始”细胞和CD45RA- CCR7-“效应记忆”细胞对Hsp90抑制最敏感，而这并未干扰它们的表型或激活状态。我们的结果表明，Hsp90是HIV-1潜伏的主要调节因子，在治愈策略中可能是潜在的靶向目标。
