References
-
Calado, M. et al. Unravelling the triad of neuroinvasion, neurodissemination, and neuroinflammation of human immunodeficiency virus type 1 in the central nervous system. Rev. Med. Virol. 34, e2534. https://doi.org/10.1002/rmv.2534 (2024).
-
Fattakhov, N., Torices, S., Stangis, M., Park, M. & Toborek, M. Synergistic impairment of the neurovascular unit by HIV-1 infection and methamphetamine use implications for HIV-1-associated neurocognitive disorders. Viruses 13(9), 1889. https://doi.org/10.3390/v13091883 (2021).
-
Osborne, O., Peyravian, N., Nair, M., Daunert, S. & Toborek, M. The paradox of HIV blood-brain barrier penetrance and antiretroviral drug delivery deficiencies. Trends Neurosci. 43, 695–708. https://doi.org/10.1016/j.tins.2020.06.007 (2020).
-
Zhu, Y., Verkhratsky, A., Chen, H. & Yi, C. Understanding glucose metabolism and insulin action at the blood-brain barrier: Implications for brain health and neurodegenerative diseases. Acta Physiol. (Oxf) 241, e14283. https://doi.org/10.1111/apha.14283 (2025).
-
Kadry, H., Noorani, B. & Cucullo, L. A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS 17, 69. https://doi.org/10.1186/s12987-020-00230-3 (2020).
-
Patabendige, A. & Janigro, D. The role of the blood-brain barrier during neurological disease and infection. Biochem. Soc. Trans. 51, 613–626. https://doi.org/10.1042/bst20220830 (2023).
-
Huang, X. et al. Endothelial DR6 in blood-brain barrier malfunction in Alzheimer’s disease. Cell Death Dis 15, 258. https://doi.org/10.1038/s41419-024-06639-0 (2024).
-
Tsao, C. C. et al. Pericyte hypoxia-inducible factor-1 (HIF-1) drives blood-brain barrier disruption and impacts acute ischemic stroke outcome. Angiogenesis 24, 823–842. https://doi.org/10.1007/s10456-021-09796-4 (2021).
-
Greene, C. et al. Blood-brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nat. Neurosci. 27, 421–432. https://doi.org/10.1038/s41593-024-01576-9 (2024).
-
Shao, Q. et al. Zika virus infection disrupts neurovascular development and results in postnatal microcephaly with brain damage. Development 143, 4127–4136. https://doi.org/10.1242/dev.143768 (2016).
-
Jadhav, S. & Nema, V. HIV-associated neurotoxicity: The interplay of host and viral proteins. Mediators Inflamm. 2021, 1267041. https://doi.org/10.1155/2021/1267041 (2021).
-
Maubert, M. E., Wigdahl, B. & Nonnemacher, M. R. Opinion: Inhibition of blood-brain barrier repair as a mechanism in HIV-1 disease. Front Neurosci. 11, 228. https://doi.org/10.3389/fnins.2017.00228 (2017).
-
Byrnes, S. J. et al. Non-human primate models of HIV brain infection and cognitive disorders. Viruses 14, 1997. https://doi.org/10.3390/v14091997 (2022).
-
Waight, E. et al. Animal models for studies of HIV-1 brain reservoirs. J. Leukoc. Biol. 112, 1285–1295. https://doi.org/10.1002/JLB.5VMR0322-161R (2022).
-
Said, N. & Venketaraman, V. Neuroinflammation, blood-brain barrier, and HIV reservoirs in the CNS: An in-depth exploration of latency mechanisms and emerging therapeutic strategies. Viruses 17(4), 572. https://doi.org/10.3390/v17040572 (2025).
-
Adlakha, Y. K. Human 3D brain organoids: Steering the demolecularization of brain and neurological diseases. Cell Death Discov. 9, 221. https://doi.org/10.1038/s41420-023-01523-w (2023).
-
Zhang, W. et al. Microglia-containing human brain organoids for the study of brain development and pathology. Mol. Psychiatry 28, 96–107. https://doi.org/10.1038/s41380-022-01892-1 (2023).
-
Premeaux, T. A. et al. Next-generation human cerebral organoids as powerful tools to advance NeuroHIV research. MBio 12, e0068021. https://doi.org/10.1128/mBio.00680-21 (2021).
-
Dos Reis, R. S., Sant, S., Keeney, H., Wagner, M. C. E. & Ayyavoo, V. Modeling HIV-1 neuropathogenesis using three-dimensional human brain organoids (hBORGs) with HIV-1 infected microglia. Sci Rep 10, 15209. https://doi.org/10.1038/s41598-020-72214-0 (2020).
-
Kong, W. et al. Neuroinflammation generated by HIV-infected microglia promotes dysfunction and death of neurons in human brain organoids. PNAS Nexus 3, pgae179. https://doi.org/10.1093/pnasnexus/pgae179 (2024).
-
Narasipura, S. D. et al. Inflammatory responses revealed through HIV infection of microglia-containing cerebral organoids. J. Neuroinflamm. 22, 36. https://doi.org/10.1186/s12974-025-03353-2 (2025).
-
Martinez-Meza, S. et al. Antiretroviral drug therapy does not reduce neuroinflammation in an HIV-1 infection brain organoid model. J. Neuroinflamm. 22, 66. https://doi.org/10.1186/s12974-025-03375-w (2025).
-
Cakir, B. et al. Engineering of human brain organoids with a functional vascular-like system. Nat. Methods 16, 1169–1175. https://doi.org/10.1038/s41592-019-0586-5 (2019).
-
Fumado Navarro, J. et al. Cerebral organoids with integrated endothelial networks emulate the neurovascular unit and mitigate core necrosis. Adv. Sci. (Weinh). 12(43), e07256. https://doi.org/10.1002/advs.202507256 (2025).
-
Ridaura, I. E., Sorrentino, S. & Moroni, L. Parallels between the Developing vascular and neural systems: Signaling pathways and future perspectives for regenerative medicine. Adv. Sci. 8(3), 2101837. https://doi.org/10.1002/advs.202101837 (2021).
-
Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379. https://doi.org/10.1038/nature12517 (2013).
-
Xu, R. et al. Developing human pluripotent stem cell-based cerebral organoids with a controllable microglia ratio for modeling brain development and pathology. Stem Cell Rep. 16, 1923–1937. https://doi.org/10.1016/j.stemcr.2021.06.011 (2021).
-
Haenseler, W. et al. A highly efficient human pluripotent stem cell microglia model displays a neuronal-co-culture-specific expression profile and inflammatory response. Stem Cell Rep. 8, 1727–1742. https://doi.org/10.1016/j.stemcr.2017.05.017 (2017).
-
Dekkers, J. F. et al. High-resolution 3D imaging of fixed and cleared organoids. Nat. Protoc. 14, 1756–1771. https://doi.org/10.1038/s41596-019-0160-8 (2019).
-
Skylar-Scott, M. A. et al. Orthogonally induced differentiation of stem cells for the programmatic patterning of vascularized organoids and bioprinted tissues. Nat. Biomed. Eng. 6, 449–462. https://doi.org/10.1038/s41551-022-00856-8 (2022).
-
Dos Reis, R. S., Selvam, S., Wagner, M. C. E. & Ayyavoo, V. Modeling HIV-1 infection in CNS via infected monocytes using immunocompetent brain organoids. Methods Mol. Biol. 2807, 261–270. https://doi.org/10.1007/978-1-0716-3862-0_18 (2024).
-
Donadoni, M., Cakir, S., Bellizzi, A., Swingler, M. & Sariyer, I. K. Modeling HIV-1 infection and NeuroHIV in hiPSCs-derived cerebral organoid cultures. J. Neurovirol. 30, 362–379. https://doi.org/10.1007/s13365-024-01204-z (2024).
-
Sun, G. et al. Modeling human cytomegalovirus-induced microcephaly in human iPSC-derived brain organoids. Cell Rep. Med. 1, 100002. https://doi.org/10.1016/j.xcrm.2020.100002 (2020).
-
Ding, Y. et al. ETV2 overexpression promotes efficient differentiation of pluripotent stem cells to endothelial cells. Biotechnol. Bioeng. 122, 1914–1928. https://doi.org/10.1002/bit.28979 (2025).
-
Dao, L. et al. Modeling blood-brain barrier formation and cerebral cavernous malformations in human PSC-derived organoids. Cell Stem Cell 31(818–833), e811. https://doi.org/10.1016/j.stem.2024.04.019 (2024).
-
Kook, M. G. et al. Generation of cortical brain organoid with vascularization by assembling with vascular spheroid. Int. J. Stem Cells 15, 85–94. https://doi.org/10.15283/ijsc21157 (2022).
-
Sun, X. Y. et al. Generation of vascularized brain organoids to study neurovascular interactions. Elife 11, e76707. https://doi.org/10.7554/eLife.76707 (2022).
-
Wahl, A. & Al-Harthi, L. HIV infection of non-classical cells in the brain. Retrovirology 20, 1. https://doi.org/10.1186/s12977-023-00616-9 (2023).
-
Williams, D. W., Eugenin, E. A., Calderon, T. M. & Berman, J. W. Monocyte maturation, HIV susceptibility, and transmigration across the blood brain barrier are critical in HIV neuropathogenesis. J. Leukoc. Biol. 91, 401–415. https://doi.org/10.1189/jlb.0811394 (2012).
-
Tsering, W. et al. Preferential clustering of microglia and astrocytes around neuritic plaques during progression of Alzheimer’s disease neuropathological changes. J Neurochem 169, e16275. https://doi.org/10.1111/jnc.16275 (2025).
-
Lee, E. S., Zhou, H. & Henderson, A. J. Endothelial cells enhance human immunodeficiency virus type 1 replication in macrophages through a C/EBP-dependent mechanism. J Virol 75, 9703–9712. https://doi.org/10.1128/JVI.75.20.9703-9712.2001 (2001).
-
Wang, H., Sun, J. & Goldstein, H. Human immunodeficiency virus type 1 infection increases the in vivo capacity of peripheral monocytes to cross the blood-brain barrier into the brain and the in vivo sensitivity of the blood-brain barrier to disruption by lipopolysaccharide. J Virol 82, 7591–7600. https://doi.org/10.1128/JVI.00768-08 (2008).
-
Hernandez, C., Gorska, A. M. & Eugenin, E. Mechanisms of HIV-mediated blood-brain barrier compromise and leukocyte transmigration under the current antiretroviral era. iscience 27, 109236. https://doi.org/10.1016/j.isci.2024.109236 (2024).
-
Henninger, D. D. et al. Cytokine-induced VCAM-1 and ICAM-1 expression in different organs of the mouse. J Immunol 158, 1825–1832 (1997).
-
Singh, V., Kaur, R., Kumari, P., Pasricha, C. & Singh, R. ICAM-1 and VCAM-1: Gatekeepers in various inflammatory and cardiovascular disorders. Clin. Chim. Acta 548, 117487. https://doi.org/10.1016/j.cca.2023.117487 (2023).
-
Li, J. et al. Development of novel therapeutics targeting the blood-brain barrier: from barrier to carrier. Adv Sci (Weinh) 8, e2101090. https://doi.org/10.1002/advs.202101090 (2021).
-
Fletcher, C. V. et al. Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proc. Natl. Acad. Sci. U S A 111, 2307–2312. https://doi.org/10.1073/pnas.1318249111 (2014).
-
Labarthe, L. et al. Pharmacokinetics and tissue distribution of tenofovir, emtricitabine and dolutegravir in mice. J. Antimicrob. Chemother. 77, 1094–1101. https://doi.org/10.1093/jac/dkab501 (2022).
-
Colon Ortiz, R. et al. Cocaine regulates antiretroviral therapy CNS access through pregnane-x receptor-mediated drug transporter and metabolizing enzyme modulation at the blood brain barrier. Fluids Barriers CNS 21, 5. https://doi.org/10.1186/s12987-023-00507-3 (2024).
-
Sun, M., Manson, M. L., Guo, T. & de Lange, E. C. M. CNS viral infections-what to consider for improving drug treatment: A plea for using mathematical modeling approaches. CNS Drugs 38, 349–373. https://doi.org/10.1007/s40263-024-01082-3 (2024).
-
Van den Hof, M. et al. CNS penetration of ART in HIV-infected children. J. Antimicrob. Chemother. 73, 484–489. https://doi.org/10.1093/jac/dkx396 (2018).
-
Cuenca, M. V., Bulut, M., Mummery, C. L. & Orlova, V. V. Vascularization of organoid microenvironments: Perfusable networks for organoid growth and maturation. Curr. Opin. Biomed. Eng. 34, 100586. https://doi.org/10.1016/j.cobme.2025.100586 (2025).
