ROLIPRAM, A SPECIFIC TYPE-IV PHOSPHODIESTERASE INHIBITOR, IS A POTENTINHIBITOR OF HIV-1 REPLICATION

Objective: To determine the effects of rolipram, a specific type IV ph osphodiesterase inhibitor, on tumor necrosis factor (TNF)-alpha produc tion and HIV-1 replication. Design: TNF-alpha enhances HIV-1 replicati on in vitro; blocking TNF-alpha and thereby inhibiting HIV-1 replicati on may therefore potentially delay progression of HIV disease. Pentoxi fylline is a non-specific phosphodiesterase inhibitor that blocks TNF- alpha synthesis and HIV-1 replication in vitro and has been shown in p reliminary clinical studies to decrease viral replication in HIV-1-inf ected patients. Rolipram, which selectively inhibits the predominant p hosphodiesterase isoenzyme of monocytes, inhibits lipopolysaccharide ( LPS)-induced TNF-alpha with 500-fold greater potency than pentoxifylli ne. We, therefore, hypothesized that rolipram would be a powerful inhi bitor of HIV-1 replication. Methods: The effects of rolipram and pento xifylline on TNF-alpha production and HIV-1 replication were determine d in infected and uninfected peripheral blood mononuclear cells (PBMC) , in a chronically infected promonocytic cell line (U1) and in an acut ely infected monocytic cell line (BT4A3.5). TNF-alpha was determined b y specific radioimmunoassay and HIV-1 replication was measured by p24 antigen and HIV-1 mRNA production. Results: Rolipram inhibited TNF-alp ha production in LPS- and phorbol myristate acetate (PMA)-stimulated P BMC and in PMA-stimulated U1 cells. Rolipram also inhibited HIV-1 repl ication in the U1 cell line, as well as in acutely infected PBMC and B T4A3.5 cells. Depending on the experimental conditions, rolipram was 1 0-600 times more potent, on a molar basis, than pentoxifylline. Conclu sion: Rolipram is a potent inhibitor HIV-1 replication and therefore d eserves further investigation as a potential therapeutic agent in the treatment of HIV-1-infected patients.