Abstract
Astrocyte dysregulation correlates with the severity and the rate of human immunodeficiency virus (HIV)-associated dementia (HAD) progression, highlighting a pivotal role for astrocytes in HIV neuropathogenesis. Yet, astrocytes limit HIV, indicating that they posses an intrinsic molecular mechanism to restrict HIV replication. We previously established that this restriction can be partly overcome by priming astrocytes with gamma interferon (IFN-γ), which is elevated in the cerebral spinal fluid of HAD patients. We evaluated the mechanism of restrictive HIV replication in astrocytes and how IFN-γ priming modulates this restriction. We demonstrate that the downstream effector of Wnt signaling, T-cell factor 4 (TCF-4), is part of a transcriptional complex that is immunoprecipitated with HIV TAR-containing region in untreated astrocytes but not in IFN-γ-treated cells. Blocking TCF-4 activity with a dominant-negative mutant enhanced HTV replication by threefold in both the astrocytoma cell line U87MG and primary fetal astrocytes. Using a TCF-4 reporter plasmid, we directly demonstrate that Wnt signaling is active in human astrocytes and is markedly reduced by IFN-γ treatment. Collectively, these data implicate TCF-4 in repressing HIV replication and the ability of IFN-γ to regulate this restriction by inhibiting TCF-4. Given that TCF-4 is the downstream effector of Wnt signaling, harnessing Wnt signaling as an intrinsic molecular mechanism to limit HIV replication may emerge as a powerful tool to regulate HTV replication within and outside of the brain.
| Original language | English |
|---|---|
| Pages (from-to) | 5864-5871 |
| Number of pages | 8 |
| Journal | Journal of Virology |
| Volume | 81 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Jun 2007 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Immunology
Cite this
Human immunodeficiency virus-restricted replication in astrocytes and the ability of gamma interferon to modulate this restriction are regulated by a downstream effector of the Wnt signaling pathway. / Carroll-Anzinger, Deborah; Kumar, Anvita; Adarichev, Vyacheslav; Kashanchi, Fatah; Al-Harthi, Lena.
In: Journal of Virology, Vol. 81, No. 11, 06.2007, p. 5864-5871.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Human immunodeficiency virus-restricted replication in astrocytes and the ability of gamma interferon to modulate this restriction are regulated by a downstream effector of the Wnt signaling pathway
AU - Carroll-Anzinger, Deborah
AU - Kumar, Anvita
AU - Adarichev, Vyacheslav
AU - Kashanchi, Fatah
AU - Al-Harthi, Lena
PY - 2007/6
Y1 - 2007/6
N2 - Astrocyte dysregulation correlates with the severity and the rate of human immunodeficiency virus (HIV)-associated dementia (HAD) progression, highlighting a pivotal role for astrocytes in HIV neuropathogenesis. Yet, astrocytes limit HIV, indicating that they posses an intrinsic molecular mechanism to restrict HIV replication. We previously established that this restriction can be partly overcome by priming astrocytes with gamma interferon (IFN-γ), which is elevated in the cerebral spinal fluid of HAD patients. We evaluated the mechanism of restrictive HIV replication in astrocytes and how IFN-γ priming modulates this restriction. We demonstrate that the downstream effector of Wnt signaling, T-cell factor 4 (TCF-4), is part of a transcriptional complex that is immunoprecipitated with HIV TAR-containing region in untreated astrocytes but not in IFN-γ-treated cells. Blocking TCF-4 activity with a dominant-negative mutant enhanced HTV replication by threefold in both the astrocytoma cell line U87MG and primary fetal astrocytes. Using a TCF-4 reporter plasmid, we directly demonstrate that Wnt signaling is active in human astrocytes and is markedly reduced by IFN-γ treatment. Collectively, these data implicate TCF-4 in repressing HIV replication and the ability of IFN-γ to regulate this restriction by inhibiting TCF-4. Given that TCF-4 is the downstream effector of Wnt signaling, harnessing Wnt signaling as an intrinsic molecular mechanism to limit HIV replication may emerge as a powerful tool to regulate HTV replication within and outside of the brain.
AB - Astrocyte dysregulation correlates with the severity and the rate of human immunodeficiency virus (HIV)-associated dementia (HAD) progression, highlighting a pivotal role for astrocytes in HIV neuropathogenesis. Yet, astrocytes limit HIV, indicating that they posses an intrinsic molecular mechanism to restrict HIV replication. We previously established that this restriction can be partly overcome by priming astrocytes with gamma interferon (IFN-γ), which is elevated in the cerebral spinal fluid of HAD patients. We evaluated the mechanism of restrictive HIV replication in astrocytes and how IFN-γ priming modulates this restriction. We demonstrate that the downstream effector of Wnt signaling, T-cell factor 4 (TCF-4), is part of a transcriptional complex that is immunoprecipitated with HIV TAR-containing region in untreated astrocytes but not in IFN-γ-treated cells. Blocking TCF-4 activity with a dominant-negative mutant enhanced HTV replication by threefold in both the astrocytoma cell line U87MG and primary fetal astrocytes. Using a TCF-4 reporter plasmid, we directly demonstrate that Wnt signaling is active in human astrocytes and is markedly reduced by IFN-γ treatment. Collectively, these data implicate TCF-4 in repressing HIV replication and the ability of IFN-γ to regulate this restriction by inhibiting TCF-4. Given that TCF-4 is the downstream effector of Wnt signaling, harnessing Wnt signaling as an intrinsic molecular mechanism to limit HIV replication may emerge as a powerful tool to regulate HTV replication within and outside of the brain.
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UR - http://www.scopus.com/inward/citedby.url?scp=34249781154&partnerID=8YFLogxK
U2 - 10.1128/JVI.02234-06
DO - 10.1128/JVI.02234-06
M3 - Article
C2 - 17392368
AN - SCOPUS:34249781154
VL - 81
SP - 5864
EP - 5871
JO - Journal of Virology
JF - Journal of Virology
SN - 0022-538X
IS - 11
ER -