Monocyte to macrophage differentiation and changes in cellular redox homeostasis promote cell type- specific HIV latency reactivation

• 成果类型: Article
• 署名作者: Blanco, Alexandra; Coronado, Robert A.; Arun, Neha; Ma, Kelly; Dar, Roy D.; Kieffer, Collin
• 署名单位: University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14679
• DOI: 10.1073/pnas.2313823121
• 发表日期: 2024-05-07
• 关键词: in-vitro; thp-1 cells; cyclin t1; thioredoxin; reservoir; tat; polarization; replication; auranofin; MODEL

摘要

HIV latency regulation in monocytes and macrophages can vary according to signals directing differentiation, polarization, and function. To investigate these processes, we generated an HIV latency model in THP- 1 monocytes and showed differential levels of HIV reactivation among clonal populations. Monocyte- to- macrophage differentiation of HIV- infected primary human CD14+ and THP- 1 cells induced HIV reactivation and showed that virus production increased concomitant with macrophage differentiation. We applied the HIV- infected THP- 1 monocyte- to- macrophage (MLat) model to assess the biological mechanisms regulating HIV latency dynamics during monocyte- to- macrophage differentiation. We pinpointed protein kinase C signaling pathway activation and Cyclin T1 upregulation as inherent differentiation mechanisms that regulate HIV latency reactivation. Macrophage polarization regulated latency, revealing proinflammatory M1 macrophages suppressed HIV reactivation while anti- inflammatory M2 macrophages promoted HIV reactivation. Because macrophages rely on reactive- oxygen species (ROS) to exert numerous cellular functions, we disrupted redox pathways and found that inhibitors of the thioredoxin (Trx) system acted as latency- promoting agents in T- cells and monocytes, but opposingly acted as latency- reversing agents in macrophages. We explored this mechanism with Auranofin, a clinical candidate for reducing HIV reservoirs, and demonstrated Trx reductase inhibition led to ROS induced NF-kappa B activity, which promoted HIV reactivation in macrophages, but not in T- cells and monocytes. Collectively, cell type- specific differences in HIV latency regulation could pose a barrier to HIV eradication strategies.