Additive effects of IL-2 and protein kinase A type I antagonist on function of T cells from HIV-infected patients on HAART.
OBJECTIVE
To explore the basis for a possible immunomodulatory combination therapy with IL-2 and agents inhibiting protein kinase A (PKA) type I.


METHODS
Highly active antiretroviral therapy (HAART) has dramatically improved HIV therapy, but fails to eradicate the virus, and the persistence of HIV-associated immunodeficiency demonstrates the need for additional immunomodulating therapies. We have previously shown that hyperactivation of PKA type I inhibits the function of HIV-infected patient T cells. The separate and combined effect of a PKA type I-selective antagonist (Rp-8-Br-cAMPS) and Interleukin (IL)-2 on the function of T cells from HIV-infected patients on HAART was examined.


METHODS
The effect of Rp-8-Br-cAMPS on anti-CD3 stimulated proliferation and IL-2 production and the combined effect with exogenous IL-2 was studied in vitro with cells from 13 HIV-infected patients on HAART and six uninfected controls.


RESULTS
The PKA type I-selective antagonist improved cell proliferation (median 1.5-fold, maximal 2.8-fold) and IL-2 production (median 1.5-fold, maximal 2.4-fold) in T cells from HIV-infected patients on HAART, but not in controls. The addition of IL-2 enhanced proliferation of T cells from HIV-infected patients (approximately 1.9-fold) and that of controls (approximately 1.4-fold), but IL-2 had no effect at the concentrations produced by treatment with PKA type I antagonist. However, the combined effect of IL-2 and PKA type I antagonist was additive and resulted in a further increase in T-cell proliferation (median 2.5-fold, maximal 5.8-fold), reaching levels comparable with those of uninfected controls in most of the patients.


CONCLUSIONS
Our findings suggest a basis for a novel strategy in treatment of HIV infection by combining IL-2 therapy and treatment modalities counteracting PKA type I activity with HAART.
Aandahl
E M
EM
Institute of Medical Biochemistry, University of Oslo, Norway.
Aukrust
P
P
Müller
F
F
Hansson
V
V
Taskén
K
K
Frøland
S S
SS
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives; D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D016022:Case-Control Studies; D002455:Cell Division / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000008:administration & dosage*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D013873:Thionucleotides / Q000008:administration & dosage
C105593:8-bromoadenosine-3',5'-cyclic monophosphorothioate; D000276:Adjuvants, Immunologic; D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D013873:Thionucleotides; D015124:8-Bromo Cyclic Adenosine Monophosphate; D017868:Cyclic AMP-Dependent Protein Kinases