Amplification of the signal transducer and activator of transcription I signaling pathway and its association with apoptosis in monocytes from HIV-infected patients.
BACKGROUND
Monocytes/macrophages play a major role in inflammation and pathogen clearance. However, chronic immune activation observed during HIV infection may also cause cellular dysfunction and tissue pathology. Indeed, several defects have been reported in these cells during HIV infections. As cytokine responsiveness via the signal transducer and activator of transcription (STAT1) signaling pathway is critical for these functions, we hypothesized that its activation in monocytes from HIV-positive patients may be disrupted.


OBJECTIVE
To evaluate cytokine-dependent STAT signaling in monocytes from HIV-positive patients and study the biological impact and molecular mechanisms responsible for the alterations in the interferon (IFN)-gamma-induced STAT1 pathway observed.


METHODS
Monocytes from chronically infected HIV-positive patients on and off antiretroviral therapy were assayed respectively for STAT activation, apoptosis, and other downstream effects by flow cytometry, real-time PCR and enzyme-linked immunosorbent assay.


RESULTS
Unlike IFN-alpha, interleukin-10, granulocyte macrophage colony-stimulating factor, and interleukin-4, only IFN-gamma-induced STAT1 activation was upregulated in monocytes from off-therapy patients compared with those on antiretroviral therapy and HIV-negative controls, correlating with increased total STAT1 expression. Among the IFN-gamma responsive genes (IRF-1, CXCL9, CXCL10) studied, differential effects were observed, likely reflecting the more complex regulatory control over their expression. Interestingly, spontaneous monocyte apoptosis was elevated in HIV-positive patients off-therapy compared with HIV-negative controls and correlated with STAT1 expression. IFN-gamma-induced apoptosis was also increased and persisted despite seemingly effective antiretroviral therapy.


CONCLUSIONS
Amplification of STAT1 signaling and apoptosis may reflect the chronic nature of immune activation in HIV-positive patients and contribute to the functional impairment observed in monocytes through the course of the disease.
Alhetheel
Abdulkarim
A
Infectious Disease and Vaccine Research Centre, Children's Hospital of Eastern Ontario - Research Institute, Canada.
Yakubtsov
Yuriy
Y
Abdkader
Khaled
K
Sant
Nadia
N
Diaz-Mitoma
Francisco
F
Kumar
Ashok
A
Kryworuchko
Marko
M
D017209:Apoptosis / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D015854:Up-Regulation
D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human