Rader Anusca G, Cloherty Alexandra P M, Patel Kharishma S, Almandawi Dima D A, Pajkrt Dasja, Wolthers Katja C, Sridhar Adithya, van Piggelen Sterre, Baaij Liselotte E, Schreurs Renée R C E, Ribeiro Carla M S
Amsterdam UMC, location University of Amsterdam, Experimental Immunology, Amsterdam, The Netherlands.
Amsterdam institute for Immunology & Infectious Diseases, Amsterdam, The Netherlands.
PLoS Pathog. 2024 Dec 27;20(12):e1012714. doi: 10.1371/journal.ppat.1012714. eCollection 2024 Dec.
The gastrointestinal tract is a prominent portal of entry for HIV-1 during sexual or perinatal transmission, as well as a major site of HIV-1 persistence and replication. Elucidation of underlying mechanisms of intestinal HIV-1 infection are thus needed for the advancement of HIV-1 curative therapies. Here, we present a human 2D intestinal immuno-organoid system to model HIV-1 disease that recapitulates tissue compartmentalization and epithelial-immune cellular interactions. Our data demonstrate that apical exposure of intestinal epithelium to HIV-1 results in viral internalization, with subsequent basolateral shedding of replication-competent viruses, in a manner that is impervious to antiretroviral treatment. Incorporation of subepithelial dendritic cells resulted in HIV-1 luminal sampling and amplification of residual viral replication of lab-adapted and transmitted-founder (T/F) HIV-1 variants. Markedly, intraepithelial viral capture ensued an altered distribution of specialized endosomal pathways alongside durable sequestration of infectious HIV-1 within lysobisphosphatidic acid (LPBA)-rich vesicles. Therapeutic neutralization of LBPA-dependent trafficking limited productive HIV-1 infection, and thereby demonstrated the pivotal role of intraepithelial multivesicular endosomes as niches for virulent HIV-1 within the intestinal mucosa. Our study showcases the application of primary human 2D immune-competent organoid cultures in uncovering mechanisms of intestinal HIV-1 disease as well as a platform for preclinical antiviral drug discovery.
胃肠道是HIV-1在性传播或围产期传播过程中的一个重要进入门户，也是HIV-1持续存在和复制的主要部位。因此，为了推进HIV-1治愈疗法，需要阐明肠道HIV-1感染的潜在机制。在这里，我们展示了一种人类二维肠道免疫类器官系统，用于模拟HIV-1疾病，该系统概括了组织分区和上皮-免疫细胞相互作用。我们的数据表明，肠道上皮细胞顶端暴露于HIV-1会导致病毒内化，随后具有复制能力的病毒从基底外侧脱落，这种方式对抗逆转录病毒治疗不敏感。上皮下树突状细胞的加入导致HIV-1在管腔中取样，并扩增实验室适应型和传播奠基者（T/F）HIV-1变体的残余病毒复制。值得注意的是，上皮内病毒捕获伴随着特殊内体途径分布的改变，以及感染性HIV-1在富含溶血双磷脂酸（LBPA）的囊泡中的持久隔离。对LBPA依赖性运输的治疗性中和限制了HIV-1的有效感染，从而证明了上皮内多囊泡内体作为肠道粘膜中致病性HIV-1的生态位的关键作用。我们的研究展示了原代人类二维免疫活性类器官培养在揭示肠道HIV-1疾病机制方面的应用，以及作为临床前抗病毒药物发现的平台。
