Leukemia inhibitor factor (LIF) inhibits HIV-1 replication via restriction of stat 3 activation.
Leukemia inhibitor factor (LIF) has been shown to potently inhibit HIV-1 replication in vitro and in human organ explant cultures. Furthermore, LIF activates the Jak/Stat signaling pathway with which many viruses, including HIV-1, interfere. We used CXCR4 and the LIF signaling receptor (gp130)-expressing cMAGI cells transfected with CD4, CCR5, and HIV-LTR-beta-galactosidase as a model system to investigate the potential involvement of Stat proteins in the anti-HIV-1 effect of LIF. Pretreatment with recombinant human (rh)LIF resulted in a significantly reduced uptake of HIV-1(BaL) , HIV-1(LAI), and SIVmac251 viral particles without affecting uptake of murine leukemia retroviral particles. HIV-1(BaL), HIV-1(LAI), as well as rhLIF selectively induced phosphorylation of Stat 3 but not Stat 1 or Stat 5. However, treatment of cMAGI cells with rhLIF prior to HIV-1 infection downregulated the HIV-1-mediated Stat 3 phosphorylation. In addition, peripheral blood mononuclear cells (PBMCs) transfected with Stat 3 siRNA prior to HIV-1(LAI) or HIV-1(BaL) infection produced significantly less HIV-1 p24 antigen as compared to nontransfected HIV-1(LAI) and HIV-1(BaL)-infected PBMCs. Thus, the Jak/Stat signaling pathway is important for the HIV-1 replication life cycle and rhLIF excerts its anti-HIV-1 activity by disrupting this signaling cascade.
Tjernlund
Annelie
A
Center for Infectious Medicine, Department of Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden. Annelie.Tjernlund@ki.se
Walther-Jallow
Lilian
L
Behbahani
Homira
H
Screpanti
Valentina
V
Nowak
Piotr
P
Grandien
Alf
A
Andersson
Jan
J
Patterson
Bruce K
BK
D045744:Cell Line, Tumor; D016655:HIV Core Protein p24 / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D053605:Leukemia Inhibitory Factor / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000821:virology*; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D014779:Virus Replication / Q000276:immunology* / Q000502:physiology*
D016655:HIV Core Protein p24; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor