Human Brain Organoid Models for NeuroHIV and Anti-HIV Research

The persistence of human immunodeficiency virus type 1 (HIV-1) in the central nervous system (CNS) remains a major barrier to a cure and a key driver of HIV-associated neurocognitive disorders (HAND). For decades, progress in understanding HIV-1 neuropathogenesis has been limited by the lack of experimental models capable of recapitulating the complexity of the human brain. The development of three-dimensional (3D) brain organoids derived from human induced pluripotent stem cells (iPSCs) has significantly advanced the field by providing a physiologically relevant and clinically translatable platform for studying HIV-1 infection in the CNS. This review summarizes the evolution of brain organoid technologies, from self-organizing cultures to immune-competent organoids and multi-region assembloids. We highlight their contributions to understanding HIV-1 neuroinflammation, neuronal injury, and CNS reservoir establishment. We also discuss emerging advances integrating organoids with bioengineering and single-cell omics approaches to overcome current limitations and accelerate the development of therapeutic and curative strategies targeting HIV-1 persistence in the CNS.