The brain-specific factor FEZ1 is a determinant of neuronal susceptibility to HIV-1 infection.

Hdl Handle:
http://hdl.handle.net/10147/94042
Title:
The brain-specific factor FEZ1 is a determinant of neuronal susceptibility to HIV-1 infection.
Authors:
Haedicke, Juliane; Brown, Craig; Naghavi, Mojgan H
Affiliation:
Centre for Research in Infectious Diseases, School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.
Citation:
The brain-specific factor FEZ1 is a determinant of neuronal susceptibility to HIV-1 infection. 2009, 106 (33):14040-5 Proc. Natl. Acad. Sci. U.S.A.
Journal:
Proceedings of the National Academy of Sciences of the United States of America
Issue Date:
18-Aug-2009
URI:
http://hdl.handle.net/10147/94042
DOI:
10.1073/pnas.0900502106
PubMed ID:
19667186
Abstract:
Neurons are one of the few cell types in the human body that do not support HIV type-1 (HIV-1) replication. Although the lack of key receptors is a major obstacle to infection, studies suggest that additional functions inhibit virus replication to explain the exquisite resistance of neurons to HIV-1. However, specific neuronal factors that may explain this resistance remain to be discovered. In a screen for antiviral factors using a fibroblast line chemically mutagenized and selected for resistance to retroviral infection, we recently identified induction of rat FEZ1 (fasciculation and elongation protein zeta-1), a brain-specific protein, as the cause of this resistance. When exogenously expressed in nonneuronal cell lines rat FEZ1 blocked nuclear entry of retroviral DNA. Here, we demonstrate that among human brain cells, neurons naturally express high levels of FEZ1 compared to astrocytes or microglia cells and are correspondingly less susceptible to infection with pseudotyped HIV-1 that bypasses receptor-mediated viral entry. Demonstrating that endogenous FEZ1 was functionally important in the resistance of neurons to HIV-1 infection, siRNA-mediated knockdown of endogenous FEZ1 increased the infectivity of neurons while sensitive brain cell types like microglia became more resistant upon FEZ1 overexpression. In addition, FEZ1 expression was not induced in response to IFN treatment. As such, in contrast to other widely expressed, IFN-inducible antiviral factors, FEZ1 appears to represent a unique neuron-specific determinant of cellular susceptibility to infection in a cell type that is naturally resistant to HIV-1.
Language:
en
MeSH:
Adaptor Proteins, Signal Transducing; Animals; Astrocytes; Brain; Cell Line, Tumor; DNA, Viral; Fibroblasts; HIV Infections; HIV-1; Humans; Nerve Tissue Proteins; Neurons; RNA Interference; RNA, Small Interfering; Rats
ISSN:
1091-6490

Full metadata record

DC FieldValue Language
dc.contributor.authorHaedicke, Julianeen
dc.contributor.authorBrown, Craigen
dc.contributor.authorNaghavi, Mojgan Hen
dc.date.accessioned2010-03-10T11:36:07Z-
dc.date.available2010-03-10T11:36:07Z-
dc.date.issued2009-08-18-
dc.identifier.citationThe brain-specific factor FEZ1 is a determinant of neuronal susceptibility to HIV-1 infection. 2009, 106 (33):14040-5 Proc. Natl. Acad. Sci. U.S.A.en
dc.identifier.issn1091-6490-
dc.identifier.pmid19667186-
dc.identifier.doi10.1073/pnas.0900502106-
dc.identifier.urihttp://hdl.handle.net/10147/94042-
dc.description.abstractNeurons are one of the few cell types in the human body that do not support HIV type-1 (HIV-1) replication. Although the lack of key receptors is a major obstacle to infection, studies suggest that additional functions inhibit virus replication to explain the exquisite resistance of neurons to HIV-1. However, specific neuronal factors that may explain this resistance remain to be discovered. In a screen for antiviral factors using a fibroblast line chemically mutagenized and selected for resistance to retroviral infection, we recently identified induction of rat FEZ1 (fasciculation and elongation protein zeta-1), a brain-specific protein, as the cause of this resistance. When exogenously expressed in nonneuronal cell lines rat FEZ1 blocked nuclear entry of retroviral DNA. Here, we demonstrate that among human brain cells, neurons naturally express high levels of FEZ1 compared to astrocytes or microglia cells and are correspondingly less susceptible to infection with pseudotyped HIV-1 that bypasses receptor-mediated viral entry. Demonstrating that endogenous FEZ1 was functionally important in the resistance of neurons to HIV-1 infection, siRNA-mediated knockdown of endogenous FEZ1 increased the infectivity of neurons while sensitive brain cell types like microglia became more resistant upon FEZ1 overexpression. In addition, FEZ1 expression was not induced in response to IFN treatment. As such, in contrast to other widely expressed, IFN-inducible antiviral factors, FEZ1 appears to represent a unique neuron-specific determinant of cellular susceptibility to infection in a cell type that is naturally resistant to HIV-1.-
dc.language.isoenen
dc.subject.meshAdaptor Proteins, Signal Transducing-
dc.subject.meshAnimals-
dc.subject.meshAstrocytes-
dc.subject.meshBrain-
dc.subject.meshCell Line, Tumor-
dc.subject.meshDNA, Viral-
dc.subject.meshFibroblasts-
dc.subject.meshHIV Infections-
dc.subject.meshHIV-1-
dc.subject.meshHumans-
dc.subject.meshNerve Tissue Proteins-
dc.subject.meshNeurons-
dc.subject.meshRNA Interference-
dc.subject.meshRNA, Small Interfering-
dc.subject.meshRats-
dc.titleThe brain-specific factor FEZ1 is a determinant of neuronal susceptibility to HIV-1 infection.en
dc.contributor.departmentCentre for Research in Infectious Diseases, School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.en
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of Americaen
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