TY - JOUR
T1 - Characterization of HIV-1 Infection in Microglia-Containing Human Cerebral Organoids
AU - Gumbs, Stephanie B.H.
AU - Berdenis van Berlekom, Amber
AU - Kübler, Raphael
AU - Schipper, Pauline J.
AU - Gharu, Lavina
AU - Boks, Marco P.
AU - Ormel, Paul R.
AU - Wensing, Annemarie M.J.
AU - de Witte, Lot D.
AU - Nijhuis, Monique
N1 - Funding Information:
Funding: This research was funded by Aidsfonds grant numbers P-13204 and P-37203, Health Holland grant numbers LSHM2OO12-SGF and LSHM19101-SGF, and NIMH grant number R21MH120581.
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/4/16
Y1 - 2022/4/16
N2 - The achievement of an HIV cure is dependent on the eradication or permanent silencing of HIV-latent viral reservoirs, including the understudied central nervous system (CNS) reservoir. This requires a deep understanding of the molecular mechanisms of HIV's entry into the CNS, latency establishment, persistence, and reversal. Therefore, representative CNS culture models that reflect the intercellular dynamics and pathophysiology of the human brain are urgently needed in order to study the CNS viral reservoir and HIV-induced neuropathogenesis. In this study, we characterized a human cerebral organoid model in which microglia grow intrinsically as a CNS culture model to study HIV infection in the CNS. We demonstrated that both cerebral organoids and isolated organoid-derived microglia (oMG), infected with replication-competent HIVbal reporter viruses, support productive HIV infection via the CCR5 co-receptor. Productive HIV infection was only observed in microglial cells. Fluorescence analysis revealed microglia as the only HIV target cell. Susceptibility to HIV infection was dependent on the co-expression of microglia-specific markers and the CD4 and CCR5 HIV receptors. Altogether, this model will be a valuable tool within the HIV research community to study HIV-CNS interactions, the underlying mechanisms of HIV-associated neurological disorders (HAND), and the efficacy of new therapeutic and curative strategies on the CNS viral reservoir.
AB - The achievement of an HIV cure is dependent on the eradication or permanent silencing of HIV-latent viral reservoirs, including the understudied central nervous system (CNS) reservoir. This requires a deep understanding of the molecular mechanisms of HIV's entry into the CNS, latency establishment, persistence, and reversal. Therefore, representative CNS culture models that reflect the intercellular dynamics and pathophysiology of the human brain are urgently needed in order to study the CNS viral reservoir and HIV-induced neuropathogenesis. In this study, we characterized a human cerebral organoid model in which microglia grow intrinsically as a CNS culture model to study HIV infection in the CNS. We demonstrated that both cerebral organoids and isolated organoid-derived microglia (oMG), infected with replication-competent HIVbal reporter viruses, support productive HIV infection via the CCR5 co-receptor. Productive HIV infection was only observed in microglial cells. Fluorescence analysis revealed microglia as the only HIV target cell. Susceptibility to HIV infection was dependent on the co-expression of microglia-specific markers and the CD4 and CCR5 HIV receptors. Altogether, this model will be a valuable tool within the HIV research community to study HIV-CNS interactions, the underlying mechanisms of HIV-associated neurological disorders (HAND), and the efficacy of new therapeutic and curative strategies on the CNS viral reservoir.
KW - central nervous system
KW - HIV
KW - HIV-associated neurocognitive disorder
KW - matrigel
KW - microglia
KW - neuropathogenesis
KW - organoid
UR - http://www.scopus.com/inward/record.url?scp=85128801992&partnerID=8YFLogxK
U2 - 10.3390/v14040829
DO - 10.3390/v14040829
M3 - Article
C2 - 35458559
AN - SCOPUS:85128801992
SN - 1999-4915
VL - 14
SP - 1
EP - 20
JO - Viruses
JF - Viruses
IS - 4
M1 - 829
ER -