Increased cAMP levels and protein kinase (PKA) type I activation in CD4+ T cells and B cells contribute to the retrovirus‐induced immunodeficiency of mice (MAIDS). A useful in vivo model for drug testing in PKA type I‐ induced immunodeficiency

Abstract

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.

Mice with Disrupted Type I Protein Kinase A Anchoring in T Cells Resist Retrovirus-Induced Immunodeficiency

“…Hyperactivation of the cAMP-type I PKA pathway has been implicated in the T cell dysfunction associated with HIV infection (18) and a subset of common variable immunodeficiency (58), and is also involved in the T cell dysfunction in MAIDS (16,17).…”

“…The ability of T cells to proliferate in response to CD3 stimulation declines progressively during the course of MAIDS, partially because of high intracellular levels of cAMP and the resulting type I PKA-mediated inhibition of T cell activation (16,17). In this study, lymph node cells from LP-BM5-infected RIADtransgenic mice and sex-matched wild-type littermates were stimulated with soluble CD3 Ab and/or IL-2 for 72 h and proliferation assessed as [ 3 H]thymidine incorporation.…”

“…7A, middle and left panels). We have previously shown that the loss of CD90.2 correlates with increased intracellular cAMP concentration and activation of type I PKA (16). To examine the CD4 + CD90.…”

“…The disease is characterized by initial lymphoproliferation affecting both T and B cells, hypergammaglobulinemia, development of splenomegaly and lymphadenopathy, followed by severe T cell anergy and immunodeficiency, leading to increased susceptibility to opportunistic infections, neoplasms, and ultimately death at 16-24 wk postinfection. Hyperactivation of the cAMP-type I PKA pathway is involved in the T cell dysfunction in MAIDS (16,17), as well as HIV infection (18). Blocking this pathway partially restores T cell function in vitro in MAIDS (16,17) and in HIV infection (18).…”

“…Hyperactivation of the cAMP-type I PKA pathway is involved in the T cell dysfunction in MAIDS (16,17), as well as HIV infection (18). Blocking this pathway partially restores T cell function in vitro in MAIDS (16,17) and in HIV infection (18). Thus, although the MAIDS model is quite distinct from the virology and biology implicated in HIV infection, it is a suitable model for *The Biotechnology Center of Oslo, University of Oslo, N-0317 Oslo, Norway; the cAMP-and type I PKA-mediated T cell dysfunction of HIV infection.…”