Three-dimensional (3D) human tissue models/microphysiological systems (e.g., organs-on-chips, organoids, and tissue explants) model HIV and related comorbidities and have potential to address critical questions, including characterization of viral reservoirs, insufficient innate and adaptive immune responses, biomarker discovery and evaluation, medical complexity with comorbidities (e.g., tuberculosis and SARS-CoV-2), and protection and transmission during pregnancy and birth. Composed of multiple primary or stem cell-derived cell types organized in a dedicated 3D space, these systems hold unique promise for better reproducing human physiology, advancing therapeutic development, and bridging the human–animal model translational gap. Here, we discuss the promises and achievements with 3D human tissue models in HIV and comorbidity research, along with remaining barriers with respect to cell biology, virology, immunology, and regulatory issues.

三维 (3D) 人体组织模型/微生理系统（例如芯片上的器官、类器官和组织外植体）可对 HIV 和相关合并症进行建模，并有可能解决关键问题，包括病毒库的表征、先天性和适应性不足免疫反应、生物标志物发现和评估、合并症的医疗复杂性（例如结核病和 SARS-CoV-2）以及怀孕和分娩期间的保护和传播。这些系统由在专用 3D 空间中组织的多种原代细胞或干细胞衍生细胞类型组成，具有独特的前景，可以更好地再现人类生理学、推进治疗开发并弥合人类与动物模型转化的差距。在这里，我们讨论 3D 人体组织模型在 HIV 和合并症研究中的前景和成就，以及细胞生物学、病毒学、免疫学和监管问题方面仍然存在的障碍。