Ghneim Khader, Ten-Caten Felipe, Santana Ana Carolina, Latif Muhammad Bilal, Dinamarca Diego Andres Diaz, García-Salum Tamara, Estrada Perla Mariana Del Rio, Sohal Puja, Strongin Zachary, Harper Justin, Jean Sherrie, Wallace Chelsea, Balderas Robert, Lifson Jeffrey D, Raghunathan Gopalan, Rimmer Eric, Pastuskova Cinthia, Wu Guoxin, Micci Luca, Sieben Luiz Felipe Martins, Gerum Pedro Cesar Lopes, Dos Santos Jessica, Netea Mihai G, van der Ven Andre, Silvestri Guido, Hazuda Daria J, Gorman Daniel M, Howell Bonnie J, Sharma Ashish A, Paiardini Mirko, Soudeyns Hugo, Ribeiro Susan Pereira, Sekaly Rafick P
Pathology Advanced Translational Research Unit (PATRU), Department of Pathology and Laboratory Medicine, Emory University School of Medicine, GA, USA.
Division of Microbiology and Immunology, Emory National Primate Research Center, Emory University, Atlanta, GA, USA.
Res Sq. 2025 Mar 19:rs.3.rs-5626892. doi: 10.21203/rs.3.rs-5626892/v1.
Immunotherapeutic approaches to eliminate latently HIV-infected cells are focused on the adaptive immune system. Herein we provide mechanistic evidence for a molecular cascade characterized by epigenetic reprogramming of innate myeloid cells and CD4 T cells. The coordinate regulation and gene expression mediated by transcription factors (TFs) IRF3, IRF7, STAT1 and C/EBPβ AP-1, promoted the development of innate antiviral immunity in these cells which was associated with control of viral load and decay of cell associated viral DNA (CA-vDNA) following analytical treatment interruption (ATI) in SIV-infected rhesus macaques (RMs) treated with anti-IL-10 and anti-PD-1. The prevalence of TGF-β/SMAD signaling in a subset of combo-treated RMs with high CA-vDNA (CA-vDNA) suppressed this antiviral activity through histone deacetylases, including HDAC11, as the latter reduced chromatin accessibility of IRFs and STATs and impeded their antiviral functions. The addition of HDAC inhibitors restored antiviral response in the presence of TGF-β. Induction of IL-6, a target gene of C/EBPβ, in CA-vDNA RMs, amplified the antiviral network through IRF9, a transcription factor upstream of IRF7. We identified a similar molecular cascade in HIV elite controllers, who maintain low to undetectable viremia and small viral reservoirs without treatment. These data highlight the importance of epigenetic regulation of the host in shaping innate antiviral immune responses that control viral rebound following ATI and reduce the viral reservoir, providing insight into potential strategies for HIV cure interventions.
消除潜伏感染HIV细胞的免疫治疗方法主要集中在适应性免疫系统。在此，我们提供了一个分子级联的机制证据，其特征是先天性髓样细胞和CD4 T细胞的表观遗传重编程。由转录因子IRF3、IRF7、STAT1和C/EBPβ AP-1介导的协同调节和基因表达，促进了这些细胞中先天性抗病毒免疫的发展，这与感染SIV的恒河猴（RM）在接受抗IL-10和抗PD-1治疗后进行分析性治疗中断（ATI）时病毒载量的控制以及细胞相关病毒DNA（CA-vDNA）的衰减有关。在一部分CA-vDNA水平高的联合治疗RM中，TGF-β/SMAD信号通路的普遍存在通过组蛋白脱乙酰酶（包括HDAC11）抑制了这种抗病毒活性，因为后者降低了IRF和STAT的染色质可及性并阻碍了它们的抗病毒功能。添加HDAC抑制剂可在TGF-β存在的情况下恢复抗病毒反应。在CA-vDNA RM中诱导C/EBPβ的靶基因IL-6，通过IRF7上游的转录因子IRF9放大了抗病毒网络。我们在HIV精英控制者中发现了类似的分子级联，他们在未经治疗的情况下维持低至检测不到的病毒血症和小的病毒储存库。这些数据突出了宿主表观遗传调控在塑造先天性抗病毒免疫反应中的重要性，这种免疫反应控制了ATI后的病毒反弹并减少了病毒储存库，为HIV治愈干预的潜在策略提供了见解。
