Neuroinflammation and EIF2 Signaling Persist despite Antiretroviral Treatment in an hiPSC Tri-culture Model of HIV Infection.
Stem Cell Reports
; 14(4): 703-716, 2020 04 14.
Article
em En
| MEDLINE
| ID: mdl-32220329
ABSTRACT
HIV-associated neurocognitive disorders (HAND) affect over half of HIV-infected individuals, despite antiretroviral therapy (ART). Therapeutically targetable mechanisms underlying HAND remain elusive, partly due to a lack of a representative model. We developed a human-induced pluripotent stem cell (hiPSC)-based model, independently differentiating hiPSCs into neurons, astrocytes, and microglia, and systematically combining to generate a tri-culture with or without HIV infection and ART. Single-cell RNA sequencing analysis on tri-cultures with HIV-infected microglia revealed inflammatory signatures in the microglia and EIF2 signaling in all three cell types. Treatment with the antiretroviral compound efavirenz (EFZ) mostly resolved these signatures. However, EFZ increased RhoGDI and CD40 signaling in the HIV-infected microglia. This activation was associated with a persistent increase in transforming growth factor α production by microglia. This work establishes a tri-culture that recapitulates key features of HIV infection in the CNS and provides a new model to examine the effects of infection, its treatment, and other co-morbid conditions.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fator de Iniciação 2 em Eucariotos
/
Infecções por HIV
/
Microglia
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Células-Tronco Pluripotentes Induzidas
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Neurônios
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Stem Cell Reports
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos