HIV-1 gp120 induces anergy in naive T lymphocytes through CD4-independent protein kinase-A-mediated signaling

Journal of Leukocyte Biology

Adriana Gallo²  Veronica De Rosa¹  Anna Maria Masci¹  Silvana Cassano²  Serafino Zappacosta¹  Salvatore De Simone²  Luigi Racioppi¹  Mario Galgani¹ 

[1] Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Naples, Italy; and Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Naples, Italy; and Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Naples, Italy; and;Istituto di Endocrinologia ed Oncologia Sperimentale, Napoli, Italy Istituto di Endocrinologia ed Oncologia Sperimentale, Napoli, Italy Istituto di Endocrinologia ed Oncologia Sperimentale, Napoli, Italy

关键词: CXCR4;    HIVenv;    cAMP;    CREB;   

DOI  :  10.1189/jlb.0503239

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

The ability of the envelope glycoprotein gp120 [human immunodeficiency virus (HIV) env] to induce intracellular signals is thought to contribute to HIV-1 pathogenesis. In the present study, we found that the exposure of CD4+ CD45RA+ naive T cells to HIVenv results in a long-lasting hyporesponsiveness to antigen stimulation. This phenomenon is not dependent on CD4-mediated signals and also can be generated by the exposure of naive T cell to soluble CD4-HIVenv complexes. The analysis of the proximal signaling reveals that HIVenv does not activate Lck as well as the mitogen-activated protein kinase intermediate cascade. Conversely, the envelope glycoprotein stimulates the cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) activity and induces the progressive accumulation of the phosphorylated form of the cAMP-responsive element binding. Of note, the ligation of CXCR4 by stromal cell-derived factor-1α but not the engagement of CD4 by monoclonal antibody stimulates the PKA activity and induces a long-lasting hyporesponsivity state in naive CD4+ lymphocytes. The pretreatment of lymphocytes with H89, a cell-permeable PKA inhibitor, prevents the induction of anergy. These findings reveal a novel mechanism by which HIVenv may modulate the processes of clonal expansion, homeostatic proliferation, and terminal differentiation of the naive T lymphocyte subset.

【 授权许可】

Unknown