Anti-CD45RO suppresses human immunodeficiency virus type 1 replication in microglia

Role of Hck tyrosine kinase and implications for AIDS dementia

Mee Ohk Kim, Hyeon Sook Suh, Qiusheng Si, Bruce I. Terman, Sunhee C. Lee

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Macrophages and microglia are productively infected by HIV-1 and play a pivotal role in the pathogenesis of AIDS dementia. Although macrophages and microglia express CD45, a transmembrane protein tyrosine phosphatase, whether modulation of its activity affects human immunodeficiency virus type 1 (HIV-1) replication is unknown. Here, we report that of the five human CD45 isoforms, microglia express CD45RB and CD45RO (RB > RO) and treatment of microglia with a CD45 agonist antibody αCD45RO (UCHL-1) inhibits HIV-1 replication. αCD45RO prevented HIV-1 negative factor (Nef)-induced autophosphorylation of hematopoietic cell kinase (Hck), a myeloid lineage-specific Src kinase. Recombinant CD45 protein also inhibited HIV-1-induced Hck phosphorylation in microglia. Antennapedia-mediated delivery of Hck Src homology domain 3 (SH3), a domain that binds to the Nef PxxP motif with high affinity, reduced HIV-1-induced Hck phosphorylation and HIV-1 production in microglia. HIV-1-induced LTR transactivation was observed in U38 cells stably overexpressing wild-type Hck but not kinase-inactive Hck. In microglia, αCD45RO reduced activation of transcription factors (NF-κB and CCAAT enhancer binding protein) necessary for LTR transactivation in macrophages. These results establish that in myeloid lineage cells, Nef interacts with the Hck SH3 domain, resulting in autophosphorylation of Hck and an increase in HIV-1 transcription. αCD45RO-mediated inhibition of HIV-1 replication in microglia identifies the CD45 protein tyrosine phosphatase as a potential therapeutic target for HIV-1 infection/AIDS dementia.

Original languageEnglish (US)
Pages (from-to)62-72
Number of pages11
JournalJournal of Virology
Volume80
Issue number1
DOIs
StatePublished - Jan 2006

Fingerprint

Proto-Oncogene Proteins c-hck
dementia
neuroglia
Microglia
Virus Replication
Human immunodeficiency virus 1
Protein-Tyrosine Kinases
tyrosine
Dementia
HIV-1
phosphotransferases (kinases)
Acquired Immunodeficiency Syndrome
cells
protein-tyrosine-phosphatase
Protein Tyrosine Phosphatases
macrophages
src Homology Domains
protein phosphorylation
Macrophages
transcriptional activation

ASJC Scopus subject areas

  • Immunology

Cite this

Anti-CD45RO suppresses human immunodeficiency virus type 1 replication in microglia : Role of Hck tyrosine kinase and implications for AIDS dementia. / Kim, Mee Ohk; Suh, Hyeon Sook; Si, Qiusheng; Terman, Bruce I.; Lee, Sunhee C.

In: Journal of Virology, Vol. 80, No. 1, 01.2006, p. 62-72.

Research output: Contribution to journalArticle

Kim, Mee Ohk ; Suh, Hyeon Sook ; Si, Qiusheng ; Terman, Bruce I. ; Lee, Sunhee C. / Anti-CD45RO suppresses human immunodeficiency virus type 1 replication in microglia : Role of Hck tyrosine kinase and implications for AIDS dementia. In: Journal of Virology. 2006 ; Vol. 80, No. 1. pp. 62-72.
@article{94aef48017f440a7bac46f49d511cb24,
title = "Anti-CD45RO suppresses human immunodeficiency virus type 1 replication in microglia: Role of Hck tyrosine kinase and implications for AIDS dementia",
abstract = "Macrophages and microglia are productively infected by HIV-1 and play a pivotal role in the pathogenesis of AIDS dementia. Although macrophages and microglia express CD45, a transmembrane protein tyrosine phosphatase, whether modulation of its activity affects human immunodeficiency virus type 1 (HIV-1) replication is unknown. Here, we report that of the five human CD45 isoforms, microglia express CD45RB and CD45RO (RB > RO) and treatment of microglia with a CD45 agonist antibody αCD45RO (UCHL-1) inhibits HIV-1 replication. αCD45RO prevented HIV-1 negative factor (Nef)-induced autophosphorylation of hematopoietic cell kinase (Hck), a myeloid lineage-specific Src kinase. Recombinant CD45 protein also inhibited HIV-1-induced Hck phosphorylation in microglia. Antennapedia-mediated delivery of Hck Src homology domain 3 (SH3), a domain that binds to the Nef PxxP motif with high affinity, reduced HIV-1-induced Hck phosphorylation and HIV-1 production in microglia. HIV-1-induced LTR transactivation was observed in U38 cells stably overexpressing wild-type Hck but not kinase-inactive Hck. In microglia, αCD45RO reduced activation of transcription factors (NF-κB and CCAAT enhancer binding protein) necessary for LTR transactivation in macrophages. These results establish that in myeloid lineage cells, Nef interacts with the Hck SH3 domain, resulting in autophosphorylation of Hck and an increase in HIV-1 transcription. αCD45RO-mediated inhibition of HIV-1 replication in microglia identifies the CD45 protein tyrosine phosphatase as a potential therapeutic target for HIV-1 infection/AIDS dementia.",
author = "Kim, {Mee Ohk} and Suh, {Hyeon Sook} and Qiusheng Si and Terman, {Bruce I.} and Lee, {Sunhee C.}",
year = "2006",
month = "1",
doi = "10.1128/JVI.80.1.62-72.2006",
language = "English (US)",
volume = "80",
pages = "62--72",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "1",

}

TY - JOUR

T1 - Anti-CD45RO suppresses human immunodeficiency virus type 1 replication in microglia

T2 - Role of Hck tyrosine kinase and implications for AIDS dementia

AU - Kim, Mee Ohk

AU - Suh, Hyeon Sook

AU - Si, Qiusheng

AU - Terman, Bruce I.

AU - Lee, Sunhee C.

PY - 2006/1

Y1 - 2006/1

N2 - Macrophages and microglia are productively infected by HIV-1 and play a pivotal role in the pathogenesis of AIDS dementia. Although macrophages and microglia express CD45, a transmembrane protein tyrosine phosphatase, whether modulation of its activity affects human immunodeficiency virus type 1 (HIV-1) replication is unknown. Here, we report that of the five human CD45 isoforms, microglia express CD45RB and CD45RO (RB > RO) and treatment of microglia with a CD45 agonist antibody αCD45RO (UCHL-1) inhibits HIV-1 replication. αCD45RO prevented HIV-1 negative factor (Nef)-induced autophosphorylation of hematopoietic cell kinase (Hck), a myeloid lineage-specific Src kinase. Recombinant CD45 protein also inhibited HIV-1-induced Hck phosphorylation in microglia. Antennapedia-mediated delivery of Hck Src homology domain 3 (SH3), a domain that binds to the Nef PxxP motif with high affinity, reduced HIV-1-induced Hck phosphorylation and HIV-1 production in microglia. HIV-1-induced LTR transactivation was observed in U38 cells stably overexpressing wild-type Hck but not kinase-inactive Hck. In microglia, αCD45RO reduced activation of transcription factors (NF-κB and CCAAT enhancer binding protein) necessary for LTR transactivation in macrophages. These results establish that in myeloid lineage cells, Nef interacts with the Hck SH3 domain, resulting in autophosphorylation of Hck and an increase in HIV-1 transcription. αCD45RO-mediated inhibition of HIV-1 replication in microglia identifies the CD45 protein tyrosine phosphatase as a potential therapeutic target for HIV-1 infection/AIDS dementia.

AB - Macrophages and microglia are productively infected by HIV-1 and play a pivotal role in the pathogenesis of AIDS dementia. Although macrophages and microglia express CD45, a transmembrane protein tyrosine phosphatase, whether modulation of its activity affects human immunodeficiency virus type 1 (HIV-1) replication is unknown. Here, we report that of the five human CD45 isoforms, microglia express CD45RB and CD45RO (RB > RO) and treatment of microglia with a CD45 agonist antibody αCD45RO (UCHL-1) inhibits HIV-1 replication. αCD45RO prevented HIV-1 negative factor (Nef)-induced autophosphorylation of hematopoietic cell kinase (Hck), a myeloid lineage-specific Src kinase. Recombinant CD45 protein also inhibited HIV-1-induced Hck phosphorylation in microglia. Antennapedia-mediated delivery of Hck Src homology domain 3 (SH3), a domain that binds to the Nef PxxP motif with high affinity, reduced HIV-1-induced Hck phosphorylation and HIV-1 production in microglia. HIV-1-induced LTR transactivation was observed in U38 cells stably overexpressing wild-type Hck but not kinase-inactive Hck. In microglia, αCD45RO reduced activation of transcription factors (NF-κB and CCAAT enhancer binding protein) necessary for LTR transactivation in macrophages. These results establish that in myeloid lineage cells, Nef interacts with the Hck SH3 domain, resulting in autophosphorylation of Hck and an increase in HIV-1 transcription. αCD45RO-mediated inhibition of HIV-1 replication in microglia identifies the CD45 protein tyrosine phosphatase as a potential therapeutic target for HIV-1 infection/AIDS dementia.

UR - http://www.scopus.com/inward/record.url?scp=33645980955&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33645980955&partnerID=8YFLogxK

U2 - 10.1128/JVI.80.1.62-72.2006

DO - 10.1128/JVI.80.1.62-72.2006

M3 - Article

VL - 80

SP - 62

EP - 72

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 1

ER -