Restoration of T-cell function in HIV infection by reduction of intracellular cAMP levels with adenosine analogues.
OBJECTIVE
The impaired function of T cells is characteristic of HIV infection. It contributes to disease pathogenesis and is associated with disease prognosis. Our aim was to describe a biochemical basis for this impairment and a pharmacological way of restoring function.


METHODS
Measurement of intracellular cAMP, protein kinase A (PKA) activity and proliferative capacity of T cells to recall antigens.


RESULTS
HIV-seropositive individuals without AIDS showed significant increases in intracellular cAMP levels and PKA activity (inhibitors of lymphocyte function). The proliferative capacity of T cells to recall antigens correlated inversely with initial cAMP levels: poor proliferation was associated with high cAMP level in HIV infection. Moreover, drugs that reduced intracellular cAMP levels led to significant restoration of specific T-cell proliferation and cytotoxicity.


CONCLUSIONS
Our findings indicate that high intracellular cAMP concentrations contribute to pathogenesis of T-cell anergy in HIV infection and that drugs that decrease intracellular cAMP levels may be beneficial in the treatment of AIDS.
Hofmann
B
B
Center for Interdisciplinary Research in Immunology, UCLA School of Medicine.
Nishanian
P
P
Nguyen
T
T
Liu
M
M
Fahey
J L
JL
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000595:Amino Acid Sequence; D000946:Antigens, Fungal; D002176:Candida albicans / Q000276:immunology; D000242:Cyclic AMP / Q000378:metabolism*; D016048:Dideoxyadenosine / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007424:Intracellular Fluid / Q000378:metabolism; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry; D011494:Protein Kinases / Q000378:metabolism; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*
D000946:Antigens, Fungal; D009842:Oligopeptides; D016048:Dideoxyadenosine; C037642:kemptide; D000242:Cyclic AMP; D011494:Protein Kinases; D000241:Adenosine