Distinct expression profiles of TGF-beta1 signaling mediators in pathogenic SIVmac and non-pathogenic SIVagm infections.
BACKGROUND
The generalized T-cell activation characterizing HIV-1 and SIVmac infections in humans and macaques (MACs) is not found in the non-pathogenic SIVagm infection in African green monkeys (AGMs). We have previously shown that TGF-beta1, Foxp3 and IL-10 are induced very early after SIVagm infection. In SIVmac-infected MACs, plasma TGF-beta1 induction persists during primary infection 1. We raised the hypothesis that MACs are unable to respond to TGF-beta1 and thus cannot resorb virus-driven inflammation. We therefore compared the very early expression dynamics of pro- and anti-inflammatory markers as well as of factors involved in the TGF-beta1 signaling pathway in SIV-infected AGMs and MACs.


METHODS
Levels of transcripts encoding for pro- and anti-inflammatory markers (tnf-alpha, ifn-gamma, il-10, t-bet, gata-3) as well as for TGF-beta1 signaling mediators (smad3, smad4, smad7) were followed by real time PCR in a prospective study enrolling 6 AGMs and 6 MACs.


RESULTS
During primary SIVmac infection, up-regulations of tnf-alpha, ifn-gamma and t-bet responses (days 1-16 p.i.) were stronger whereas il-10 response was delayed (4th week p.i.) compared to SIVagm infection. Up-regulation of smad7 (days 3-8 p.i.), a cellular mediator inhibiting the TGF-beta1 signaling cascade, characterized SIV-infected MACs. In AGMs, we found increases of gata-3 but not t-bet, a longer lasting up-regulation of smad4 (days 1-21 p.i), a mediator enhancing TGF-beta1 signaling, and no smad7 up-regulations.


CONCLUSIONS
Our data suggest that the inability to resorb virus-driven inflammation and activation during the pathogenic HIV-1/SIVmac infections is associated with an unresponsiveness to TGF-beta1.
Ploquin
Mickaël J-Y
MJ
Unité de Régulation des Infections Rétrovirales, Institut Pasteur, Paris, France. mploquin@pasteur.fr
Desoutter
Jean-François
JF
Santos
Patricia R
PR
Pandrea
Ivona
I
Diop
Ousmane M
OM
Hosmalin
Anne
A
Butor
Cécile
C
Barre-Sinoussi
Françoise
F
Müller-Trutwin
Michaela C
MC
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002522:Chlorocebus aethiops / Q000276:immunology / Q000821:virology*; D050990:GATA3 Transcription Factor / Q000097:blood / Q000235:genetics; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008251:Macaca / Q000276:immunology / Q000821:virology*; D015398:Signal Transduction; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000472:pathogenicity; D051785:Smad Proteins / Q000097:blood / Q000235:genetics; D020825:T-Box Domain Proteins; D014157:Transcription Factors / Q000097:blood / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000098815:T-bet Transcription Factor
D015415:Biomarkers; D050990:GATA3 Transcription Factor; D051785:Smad Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma