期刊
SCIENTIFIC REPORTS
卷 10, 期 1, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/s41598-020-72214-0
关键词
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资金
- Laboratory for Cognitive and Molecular Morphometry at Northwestern University [R24 NS104160]
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh
- NIH [R37CA232209]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq-Brazil)
- Latin American Scholarship Program of American Universities (Laspau)
- [U01-AI35041]
HIV-1 associated neurocognitive disorder (HAND) is characterized by neuroinflammation and glial activation that, together with the release of viral proteins, trigger a pathogenic cascade resulting in synaptodendritic damage and neurodegeneration that lead to cognitive impairment. However, the molecular events underlying HIV neuropathogenesis remain elusive, mainly due to lack of brain-representative experimental systems to study HIV-CNS pathology. To fill this gap, we developed a three-dimensional (3D) human brain organoid (hBORG) model containing major cell types important for HIV-1 neuropathogenesis; neurons and astrocytes along with incorporation of HIV-infected microglia. Both infected and uninfected microglia infiltrated into hBORGs resulting in a triculture system (MG-hBORG) that mirrors the multicellular network observed in HIV-infected human brain. Moreover, the MG-hBORG model supported productive viral infection and exhibited increased inflammatory response by HIV-infected MG-hBORGs, releasing tumor necrosis factor (TNF-alpha) and interleukin-1 (IL-1 beta) and thereby mimicking the chronic neuroinflammatory environment observed in HIV-infected individuals. This model offers great promise for basic understanding of how HIV-1 infection alters the CNS compartment and induces pathological changes, paving the way for discovery of biomarkers and new therapeutic targets.
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