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.