Cytokine networks are pre-activated in T cells from HIV-infected patients on HAART and are under the control of cAMP.
OBJECTIVE
Cytokines seem to play a critical role in HIV infection. The cAMP/protein kinase A (PKA) type I pathway is shown to be hyper-activated and contributes to T-cell immune dysfunction in HIV infection. Here, we analysed firstly the levels of cytokine gene expression in unstimulated CD3+T cells from HIV-infected patients on HAART, and secondly the regulation of cytokine and cytokine-related genes by cAMP agonist and antagonist in anti-CD3 activated T cells in order to understand their effects on cytokine networks.


METHODS
Cytokine Macro Array and real-time RT-PCR techniques were used to study cytokine gene expression in T cells of HIV-positive patients.


RESULTS
Of the cytokine-related genes analysed 45% were expressed at twofold or higher levels in unstimulated T cells from HIV-infected patients as compared with healthy controls, and one-third of these genes were hypo-responsive upon activation as compared with controls. Furthermore, cAMP modulated levels of expression of a number of cytokine-related genes differently in patient and control T cells. CXCR4, CCR5 and amphiregulin were up-regulated by cAMP agonist, whereas other cytokine-related genes including macrophage inflammatory protein 1 beta, tumour necrosis factor-alpha and lymphotoxin-beta were markedly down-regulated by cAMP agonist in T cells from both HIV-infected patients and controls. Moreover, members of the chemokine/chemokine receptor family were over-represented among genes regulated by cAMP agonist/antagonist in patient T cells.


CONCLUSIONS
Our data indicate that T cells from HIV-infected patients are in a pre-activated state and that a set of cytokine genes is hypo-responsive to activation and under tonic regulation by cAMP in these T cells.
Johansson
C Christian
CC
Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway.
Bryn
Tone
T
Yndestad
Arne
A
Eiken
Hans Geir
HG
Bjerkeli
Vigdis
V
Frøland
Stig S
SS
Aukrust
Pål
P
Taskén
Kjetil
K
D000328:Adult; D000368:Aged; D023241:Antiretroviral Therapy, Highly Active; D017252:CD3 Complex / Q000378:metabolism; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016207:Cytokines / Q000235:genetics*; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D015854:Up-Regulation
D017252:CD3 Complex; D016207:Cytokines; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases