PMID- 25008924
OWN - NLM
STAT- MEDLINE
DCOM- 20141111
LR  - 20220318
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 88
IP  - 19
DP  - 2014 Oct
TI  - HIV-1 gp120 activates the STAT3/interleukin-6 axis in primary human 
      monocyte-derived dendritic cells.
PG  - 11045-55
LID - 10.1128/JVI.00307-14 [doi]
AB  - Dendritic cells (DCs) are fundamental for the initiation of immune responses and 
      are important players in AIDS immunopathogenesis. The modulation of DC functional 
      activities represents a strategic mechanism for HIV-1 to evade immune 
      surveillance. Impairment of DC function may result from bystander effects of 
      HIV-1 envelope proteins independently of direct HIV-1 infection. In this study, 
      we report that exposure of immature monocyte-derived DCs (MDDCs) to HIV-1 R5 
      gp120 resulted in the CCR5-dependent production of interleukin-6 (IL-6) via 
      mitogen-activated protein kinase (MAPK)/NF-kappaB pathways. IL-6 in turn activated 
      STAT3 by an autocrine loop. Concomitantly, gp120 promoted an early activation of 
      STAT3 that further contributed to IL-6 induction. This activation paralleled a 
      concomitant upregulation of the STAT3 inhibitor PIAS3. Notably, STAT3/IL-6 
      pathway activation was not affected by the CCR5-specific ligand CCL4. These 
      results identify STAT3 as a key signaling intermediate activated by gp120 in 
      MDDCs and highlight the existence of a virus-induced dysregulation of the 
      IL-6/STAT3 axis. HIV-1 gp120 signaling through STAT3 may provide an explanation 
      for the impairment of DC function observed upon HIV exposure. IMPORTANCE: This 
      study provides new evidence for the molecular mechanisms and signaling pathways 
      triggered by HIV-1 gp120 in human DCs in the absence of productive infection, 
      emphasizing a role of aberrant signaling in early virus-host interaction, 
      contributing to viral pathogenesis. We identified STAT3 as a key component in the 
      gp120-mediated signaling cascade involving MAPK and NF-kappaB components and 
      ultimately leading to IL-6 secretion. STAT3 now is recognized as a key regulator 
      of DC functions. Thus, the identification of this transcription factor as a 
      signaling molecule mediating some of gp120's biological effects unveils a new 
      mechanism by which HIV-1 may deregulate DC functions and contribute to AIDS 
      pathogenesis.
CI  - Copyright (c) 2014, American Society for Microbiology. All Rights Reserved.
FAU - Del Corno, Manuela
AU  - Del Corno M
AD  - Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di 
      Sanita, Rome, Italy.
FAU - Donninelli, Gloria
AU  - Donninelli G
AD  - Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di 
      Sanita, Rome, Italy.
FAU - Varano, Barbara
AU  - Varano B
AD  - Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di 
      Sanita, Rome, Italy.
FAU - Da Sacco, Letizia
AU  - Da Sacco L
AD  - Gene Expression-Microarrays Laboratory, Bambino Gesu Children's Hospital-IRCCS, 
      Rome, Italy.
FAU - Masotti, Andrea
AU  - Masotti A
AD  - Gene Expression-Microarrays Laboratory, Bambino Gesu Children's Hospital-IRCCS, 
      Rome, Italy.
FAU - Gessani, Sandra
AU  - Gessani S
AD  - Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di 
      Sanita, Rome, Italy sandra.gessani@iss.it.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140709
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (CCR5 protein, human)
RN  - 0 (Chemokine CCL4)
RN  - 0 (HIV Envelope Protein gp120)
RN  - 0 (IL6 protein, human)
RN  - 0 (Interleukin-6)
RN  - 0 (Molecular Chaperones)
RN  - 0 (NF-kappa B)
RN  - 0 (PIAS3 protein, human)
RN  - 0 (Protein Inhibitors of Activated STAT)
RN  - 0 (Receptors, CCR5)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
RN  - 0 (gp120 protein, Human immunodeficiency virus 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Autocrine Communication
MH  - Cell Differentiation
MH  - Cells, Cultured
MH  - Chemokine CCL4/genetics/immunology
MH  - Dendritic Cells/*immunology/virology
MH  - Gene Expression Regulation
MH  - HIV Envelope Protein gp120/genetics/*immunology
MH  - HIV-1/genetics/*immunology
MH  - Host-Pathogen Interactions
MH  - Humans
MH  - Immune Evasion
MH  - Interleukin-6/genetics/*immunology
MH  - Mitogen-Activated Protein Kinases/genetics/immunology
MH  - Molecular Chaperones/genetics/immunology
MH  - Monocytes/immunology/virology
MH  - NF-kappa B/genetics/immunology
MH  - Protein Inhibitors of Activated STAT/genetics/immunology
MH  - Receptors, CCR5/genetics/immunology
MH  - STAT3 Transcription Factor/genetics/*immunology
MH  - Signal Transduction/*immunology
PMC - PMC4178808
EDAT- 2014/07/11 06:00
MHDA- 2014/11/12 06:00
PMCR- 2015/04/01
CRDT- 2014/07/11 06:00
PHST- 2014/07/11 06:00 [entrez]
PHST- 2014/07/11 06:00 [pubmed]
PHST- 2014/11/12 06:00 [medline]
PHST- 2015/04/01 00:00 [pmc-release]
AID - JVI.00307-14 [pii]
AID - 00307-14 [pii]
AID - 10.1128/JVI.00307-14 [doi]
PST - ppublish
SO  - J Virol. 2014 Oct;88(19):11045-55. doi: 10.1128/JVI.00307-14. Epub 2014 Jul 9.