Increased Camp Levels and Protein Kinase (Pka) Type I Activation in Cd4+ T Cells and B Cells Contribute to Retrovirus-Induced Immunodeficiency of Mice (Maids): A Useful in Vivo Model for Drug Testing

Murine AIDS (MAIDS) is characterized by a lymphoproliferative disease and a profound anergy, which involves mostly CD4(+) T cells. To better define the mechanisms responsible for anergy, we measured cAMP concentrations in the different lymphocyte subsets of the infected mice. CD4(+) T cells and B cells displayed a dramatic 10- to 30-fold increase of cAMP. cAMP was also significantly increased in CD8(+) T cells, although to a far lesser extent. The unusual CD4(+) CD90(-) T cells, typical of MAIDS, were characterized by a much higher cAMP level than their CD90(+) counterparts. T cells of the infected mice were much more sensitive to inhibition by the cAMP analogue 8-CPT-cAMP, which confirmed increased in vivo exposure to cAMP. In accordance with the increased cAMP levels, PKA type I was constitutively activated and its C subunit was translocated to the nucleus. Finally, the profound T-cell anergy associated with MAIDS could be reversed by treating T cells with a PKA type I-selective antagonist ex vivo. MAIDS could constitute a suitable model for the study of new pharmacological agents aimed at reversing the immunosuppressive effects of cAMP previously shown to be involved in several pathological states, including HIV infection and common variable immunodeficiency.