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J Virol, June 1998, p. 4712-4720, Vol. 72, No. 6
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Inhibition of Phosphodiesterase Type IV Suppresses Human Immunodeficiency Virus Type 1 Replication and Cytokine Production in Primary T Cells: Involvement of NF-kappa B and NFAT

Joaquín Navarro,1 Carmen Punzón,2 José Luis Jiménez,1 Eduardo Fernández-Cruz,1 Angel Pizarro,3 Manuel Fresno,2 and M. Angeles Muñoz-Fernández1,*

Department of Immunology, Hospital General Universitario Gregorio Marañón,1 Centro de Biología Molecular, CSIC-UAM Universidad Autonoma de Madrid,2 and Department of Dermatology, La Paz Hospital,3 Madrid, Spain

Received 11 August 1997/Accepted 20 February 1998

Rolipram, a phosphosdiesterase type IV-specific inhibitor, prevented p24 antigen release from anti-CD3-activated human immunodeficiency virus (HIV)-infected T cells and CD4+-cell depletion associated with viral replication in a dose-responsive manner but minimally inhibited T-cell proliferation. Moreover, rolipram reduced the production of tumor necrosis factor alpha (TNF-alpha ) and interleukin-10 (IL-10) by HIV-infected T cells. The transcriptional ability of a luciferase reporter gene under control of the HIV long terminal repeat, induced by phorbol myristic acetate plus ionomycin or by TNF-alpha , in primary T and Jurkat cells was also inhibited by rolipram. Rolipram inhibited NF-kappa B and NFAT activation induced by T-cell activation in Jurkat and primary T cells, as measured by transient transfection of reporter genes and electrophoretic mobility shift assays. Exogenous addition of TNF-alpha in the presence of rolipram restored NF-kappa B but not NFAT activation or p24 release. Addition of dibutyryl-cyclic AMP (dBcAMP) mimicked the effects of rolipram on p24 antigen release, NF-kappa B activation, and TNF-alpha secretion, but it did not affect NFAT activation or IL-10 production. The protein kinase A inhibitor KT5720 prevented the inhibition of TNF-alpha secretion but not that of HIV type 1 (HIV-1) replication caused by rolipram. Our data indicate that blockade of phosphodiesterase type IV could be of benefit against HIV-1 disease by modulating cytokine secretion and transcriptional regulation of HIV replication, and they suggest an important role of NFAT in HIV replication in primary T cells. Some of those activities cannot be ascribed solely to its ability to increase cAMP.

* Corresponding author. Mailing address: Hospital General Universitario Gregorio Marañon, Servicio de Inmunologia, c/Dr. Esquerdo 47, 28007 Madrid, Spain. Phone: 34-1-5868565. Fax: 34-1-5868018. E-mail: Mmunoz{at}trasto.cbm.uam.es.

J Virol, June 1998, p. 4712-4720, Vol. 72, No. 6
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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