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-C D3/CD28 mAbs, promotes IL-2 production and proliferation of primary CD4(+) T lymphocytes, obtained from HIV-1-seronegative donors. This effect was obs erved when Tat was immobilized on a solid support, but it was not observed with soluble Tat Such hyperactivation was accomplished by recruiting the ro lipram-sensitive cyclic nucleoside phosphodiesterase 4 and resulted in incr eased susceptibility to HIV-1 infection. Accordingly, rolipram potently inh ibited HIV-1 replication in cultures stimulated by anti-CD3/CD28 +/- Tat Th ese 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 c hemotherapy, phosphodiesterase 4.