Pivotal role of cyclic nucleoside phosphodiesterase 4 in Tat-mediated CD4+ T cell hyperactivation and HIV type 1 replication

Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14620-5. doi: 10.1073/pnas.011512398.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors
  • 3',5'-Cyclic-AMP Phosphodiesterases / metabolism
  • 3',5'-Cyclic-AMP Phosphodiesterases / physiology*
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / virology
  • Cell Division / drug effects
  • Cyclic AMP / metabolism
  • Enzyme Inhibitors / pharmacology
  • Gene Products, tat / metabolism*
  • HIV-1 / drug effects
  • HIV-1 / immunology*
  • HIV-1 / physiology
  • Humans
  • Interleukin-2 / biosynthesis
  • Intracellular Fluid / metabolism
  • Lymphocyte Activation / immunology*
  • Rolipram / pharmacology
  • Virus Replication / immunology*
  • tat Gene Products, Human Immunodeficiency Virus

Substances

  • Enzyme Inhibitors
  • Gene Products, tat
  • Interleukin-2
  • tat Gene Products, Human Immunodeficiency Virus
  • Cyclic AMP
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Rolipram