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Kunze, C. ; Börner, K.* ; Kienle, E.* ; Orschmann, T. ; Rusha, E. ; Schneider, M. ; Radivojkov-Blagojevic, M. ; Drukker, M. ; Desbordes, S.C. ; Grimm, D.* ; Brack-Werner, R.

Synthetic AAV/CRISPR vectors for blocking HIV-1 expression in persistently infected astrocytes.

Glia 66, 413-427 (2018)
Research data DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Astrocytes, the most abundant cells in the mammalian brain, perform key functions and are involved in several neurodegenerative diseases. The human immunodeficiency virus (HIV) can persist in astrocytes, contributing to the HIV burden and neurological dysfunctions in infected individuals. While a comprehensive approach to HIV cure must include the targeting of HIV-1 in astrocytes, dedicated tools for this purpose are still lacking. Here we report a novel Adeno-associated virus-based vector (AAV9P1) with a synthetic surface peptide for transduction of astrocytes. Analysis of AAV9P1 transduction efficiencies with single brain cell populations, including primary human brain cells, as well as human brain organoids demonstrated that AAV9P1 targeted terminally differentiated human astrocytes much more efficiently than neurons. We then investigated whether AAV9P1 can be used to deliver HIV-inhibitory genes to astrocytes. To this end we generated AAV9P1 vectors containing genes for HIV-1 proviral editing by CRISPR/Cas9. Latently HIV-1 infected astrocytes transduced with these vectors showed significantly diminished reactivation of proviruses, compared with untransduced cultures. Sequence analysis identified mutations/deletions in key HIV-1 transcriptional control regions. We conclude that AAV9P1 is a promising tool for gene delivery to astrocytes and may facilitate inactivation/destruction of persisting HIV-1 proviruses in astrocyte reservoirs.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Crispr/cas9 ; Hiv ; Adeno-associated Viral Vector ; Astrocytes; Central-nervous-system; Human-immunodeficiency-virus; Adenoassociated Virus; Gene-expression; Cell-lines; In-vitro; Neurocognitive Disorders; Neurological Disorders; Crispr/cas9 System; Viral Vectors
Language english
Publication Year 2018
Prepublished in Year 2017
HGF-reported in Year 2017
ISSN (print) / ISBN 0894-1491
e-ISSN 1098-1136
Journal Glia
Quellenangaben Volume: 66, Issue: 2, Pages: 413-427 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Hoboken
Reviewing status Peer reviewed
Institute(s) Institute of Virology (VIRO)
Institute of Developmental Genetics (IDG)
Institute of Stem Cell Research (ISF)
Institute of Human Genetics (IHG)
POF-Topic(s) 30203 - Molecular Targets and Therapies
30204 - Cell Programming and Repair
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Immune Response and Infection
Genetics and Epidemiology
Stem Cell and Neuroscience
PSP Element(s) G-502700-001
G-500591-001
G-500500-001
G-552400-001
G-500700-001
DOI 10.1002/glia.23254
WOS ID WOS:000417845300012
Scopus ID 85033472512
PubMed ID 29119608
Erfassungsdatum 2017-11-16
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