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HIV‐1 gp120 induces anergy in naive T lymphocytes through CD4‐independent protein kinase‐A‐mediated signaling
Author(s) -
Masci Anna Maria,
Galgani Mario,
Cassano Silvana,
De Simone Salvatore,
Gallo Adriana,
De Rosa Veronica,
Zappacosta Serafino,
Racioppi Luigi
Publication year - 2003
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0503239
Subject(s) - biology , protein kinase a , microbiology and biotechnology , t cell , signal transduction , kinase , immunology , immune system
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 HIV env 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‐HIV env complexes. The analysis of the proximal signaling reveals that HIV env 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 HIV env may modulate the processes of clonal expansion, homeostatic proliferation, and terminal differentiation of the naive T lymphocyte subset.