美国威尔康奈尔医学院R. Brad Jones小组宣布他们的研究开发出了HIV库克隆的动态抗原表达和细胞毒T细胞耐药性。该项研究成果发表在2026年2月24日出版的《自然》上。

小组分离并鉴定了真正的储层克隆（ARCs），它们在产生感染病毒的同时能够自动增殖和积累，而不会明显屈服于细胞病变。在任何时候，只有一小部分ARCs表达HIV蛋白，这种状态与保守的宿主转录程序有关，但对强效T细胞刺激具有显著的难反应性。然而，与CD8⁺细胞毒性T淋巴细胞克隆的持续共培养实质上淘汰了增殖的ARCs，揭示了对免疫压力的时间集成脆弱性。相应的离体CD8⁺ T细胞反应细胞毒性较差，体内ARCs的侵蚀发生缓慢。调节性T细胞ARC显示出明显的细胞对CTL的内在抗性——这是一个长期存在的假设，现在被直接证实——与低氧化应激有关，并与去铁胺（一种低氧应激诱导剂和fda批准的治疗药物）逆转。总的来说，该团队对储存库克隆对有效的、持续的CTL压力的脆弱性提供了新的见解，并强调了内在抗性途径作为可行的治疗靶点，为推进基于免疫的HIV治愈策略开辟了机会。

研究人员表示，克隆扩增的CD4⁺ T细胞携带有反弹能力的HIV，在ART期间持续存在终生。潜伏期被认为是病毒根除的主要障碍，并且抵抗药理学逆转，然而持续的免疫压力似乎会侵蚀储存库。最近的进展已经使研究团队得以一窥异常罕见的储存细胞，暗示了持久性的促生存特性。

附：英文原文

Title: Dynamic antigen expression and cytotoxic T cell resistance in HIV reservoir clones

Author: Ferreira, Isabella A. T. M., Herrera, Alberto, Huynh, Tan Thinh, Stone, Emily, Linden, Noemi L., Ovies, Cristian, Ren, Yanqin, Bittar, Cintia, Pal, Virender K., Naing, Ethan, Sinha, Parul, Danesh, Ali, Stevenson, Eva, Vedova, Shane, Liu, Fitty, Leyre, Louise, Shea, Skylar, Wells, Elina, Miller, Itzayana G., Canis, Marie, Teixeira, Ana Rafaela, Moir, Susan, Chun, Tae-Wook, Kovacs, Colin, Gastonguay, Madeleine S., Hill, Alison L., Genel, Shy, Zumbo, Paul, Betel, Doron, Halvas, Elias K., Lee, Guinevere Q., Scheck, Rachel, Caskey, Marina, Bieniasz, Paul D., Board, Nathan L., Nussenzweig, Michel C., Jones, R. Brad

Issue&Volume: 2026-02-24

Abstract: Clonally expanded CD4+ T-cells harboring rebound-competent HIV persist lifelong during ART1-5. Latency is considered the principal barrier to viral eradication and has resisted pharmacological reversal6,7, yet sustained immune pressure appears to erode reservoirs8-15. Recent advances have yielded glimpses into exceptionally rare reservoir-harboring cells, implicating pro-survival properties in persistence16-18. Here, we isolate and characterize authentic reservoir clones (ARCs) that robustly proliferate and accumulate while producing infectious virus, without overtly succumbing to cytopathicity. At any moment, only small fractions of ARCs expressed HIV proteins, a state associated with conserved host transcriptional programs but remarkably refractory to potent T-cell stimulation. Nevertheless, sustained co-culture with a CD8+ cytotoxic T-lymphocyte clone substantially culled proliferating ARCs, revealing time-integrated vulnerability to immune pressure. The corresponding ex vivo CD8+ T-cell response was poorly cytotoxic and in vivo erosion of ARCs occurred only slowly. A regulatory T-cell ARC displayed pronounced cell-intrinsic resistance to CTL—a longstanding hypothesis now directly demonstrated—linked to low oxidative stress and reversed with deferoxamine19, a hypoxic stress inducer and FDA-approved therapeutic. Overall, we provide novel insights into the vulnerabilities of reservoir clones to potent, sustained CTL pressure and highlight intrinsic resistance pathways as actionable therapeutic targets, opening opportunities for advancing immune-based HIV cure strategies.

DOI: 10.1038/s41586-026-10298-w

Source: https://www.nature.com/articles/s41586-026-10298-w