Pivotal role of cyclic nucleoside phosphodiesterase 4 in Tat-mediated CD4+ T cell hyperactivation and HIV type 1 replication.
We show here that HIV type 1 (HIV-1) Tat protein, in combination with anti-CD3/CD28 mAbs, promotes IL-2 production and proliferation of primary CD4(+) T lymphocytes, obtained from HIV-1-seronegative donors. This effect was observed when Tat was immobilized on a solid support, but it was not observed with soluble Tat. Such hyperactivation was accomplished by recruiting the rolipram-sensitive cyclic nucleoside phosphodiesterase 4 and resulted in increased susceptibility to HIV-1 infection. Accordingly, rolipram potently inhibited HIV-1 replication in cultures stimulated by anti-CD3/CD28 +/- Tat. These results add to the concept that decreasing Tat activity is an important addition to anti-HIV-1 therapy, and they suggest a target for anti-HIV-1 chemotherapy, phosphodiesterase 4.
Secchiero
P
P
Institute of Human Virology, University of Maryland Biotechnology Institute, 725 West Lombard Street, S307, Baltimore, MD 21201-1192, USA.
Zella
D
D
Curreli
S
S
Mirandola
P
P
Capitani
S
S
Gallo
R C
RC
Zauli
G
G
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D002455:Cell Division / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015696:Gene Products, tat / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D007424:Intracellular Fluid / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D020889:Rolipram / Q000494:pharmacology; D014779:Virus Replication / Q000276:immunology*; D054322:tat Gene Products, Human Immunodeficiency Virus
D004791:Enzyme Inhibitors; D015696:Gene Products, tat; D007376:Interleukin-2; D054322:tat Gene Products, Human Immunodeficiency Virus; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D020889:Rolipram