近日，美国加州大学Alexander Marson及其团队开发出原代人CD4+ T细胞中促HIV和抗HIV宿主因子的系统性发现。2026年4月20日，国际知名学术期刊《细胞》发表了这一成果。
课题组在原代CD4+ T细胞中采用正交全基因组CRISPR激活（CRISPRa）和CRISPR敲除筛选来系统地发现亲HIV和抗HIV宿主因子。二次集合筛选和个体扰动验证了高可信度的命中，并揭示了不同的作用机制。CRISPRa发现了多种有效的抗病毒因子，包括PI16、PPID、SHISA3和ITM2A。PI16与参与HIV细胞的宿主因子相互作用并抑制病毒进入，而PPID (Cyp40)，前病毒亲环蛋白CypA的类似物，结合衣壳并减少HIV核心的核输入。结构建模、进化分析和靶向诱变揭示了PPID介导的HIV限制所需的结构域和残基，包括增强抗病毒活性的非人灵长类同源取代。总之，这些数据定义了人类原代T细胞中hiv -宿主相互作用的功能景观，并揭示了调节感染的新机制。
据了解，促进或限制人类CD4+ T细胞中人类免疫缺陷病毒（HIV）感染的宿主因子尚未得到全面鉴定。
附：英文原文
Title: Systematic discovery of pro- and anti-HIV host factors in primary human CD4+ T cells
Author: Ujjwal Rathore, Eli Dugan, Hunter Thornton, Vigneshwari Easwar Kumar, Rama Dajani, Ryan C. Burdick, Janet M. Young, Zachary Steinhart, Reanna Lao, Krista A. Delviks-Frankenberry, Wooyoung Choi, William S. Henriques, Ignacia Echeverria, Emma Dann, Ishaan Dureja, Nandini Pathak, Maya M. Arce, Justin McKetney, Jennifer M. Umhoefer, Simrun Parulekar, Ralf Schmidt, Benjamin J. Polacco, Jason Neidleman, Mauricio Montano, Vinh Q. Nguyen, Andrej Sali, Jay A. Levy, Jeannette L. Tenthorey, Yifan Cheng, Nadia R. Roan, Danielle L. Swaney, Robyn M. Kaake, Stacie E. Dodgson, Joseph Hiatt, Vinay K. Pathak, Harmit S. Malik, Nevan J. Krogan, Alexander Marson
Issue&Volume: 2026-04-20
Abstract: Host factors that promote or restrict human immunodeficiency virus (HIV) infection in human CD4+ T cells have not been comprehensively identified. We employed orthogonal genome-wide CRISPR activation (CRISPRa) and CRISPR knockout screens in primary CD4+ T cells to discover pro- and anti-HIV host factors systematically. Secondary pooled screens and individual perturbations validated high-confidence hits and revealed diverse mechanisms of action. CRISPRa uncovered multiple potent antiviral factors, including PI16, PPID, SHISA3, and ITM2A. PI16 interacts with host factors involved in HIV fusion and inhibits viral entry, whereas PPID (Cyp40), a paralog of the proviral cyclophilin CypA, binds capsid and reduces nuclear import of the HIV core. Structural modeling, evolutionary analyses, and targeted mutagenesis revealed domains and residues required for PPID-mediated HIV restriction, including non-human primate ortholog substitutions that enhance antiviral activity. Together, these data define the functional HIV-host interaction landscape in primary human T cells and uncover new mechanisms modulating infection.
DOI: 10.1016/j.cell.2026.03.046
Source: https://www.cell.com/cell/abstract/S0092-8674(26)00382-X