       Document 0237
 DOCN  M9630237
 TI    Rolipram, a specific type IV phosphodiesterase inhibitor, is a potent
       inhibitor of HIV-1 replication.
 DT    9603
 AU    Angel JB; Saget BM; Walsh SP; Greten TF; Dinarello CA; Skolnik PR;
       Endres S; Department of Medicine, Tufts University School of Medicine,;
       Boston, Massachusetts, USA.
 SO    AIDS. 1995 Oct;9(10):1137-44. Unique Identifier : AIDSLINE MED/96098129
 AB    OBJECTIVE: To determine the effects of rolipram, a specific type IV
       phosphodiesterase inhibitor, on tumor necrosis factor (TNF)-alpha
       production and HIV-1 replication. DESIGN: TNF-alpha enhances HIV-1
       replication in vitro; blocking TNF-alpha and thereby inhibiting HIV-1
       replication may therefore potentially delay progression of HIV disease.
       Pentoxifylline is a non-specific phosphodiesterase inhibitor that blocks
       TNF-alpha synthesis and HIV-1 replication in vitro and has been shown in
       preliminary clinical studies to decrease viral replication in
       HIV-1-infected patients. Rolipram, which selectively inhibits the
       predominant phosphodiesterase isoenzyme of monocytes, inhibits
       lipopolysaccharide (LPS)-induced TNF-alpha with 500-fold greater potency
       than pentoxifylline. We, therefore, hypothesized that rolipram would be
       a powerful inhibitor of HIV-1 replication. METHODS: The effects of
       rolipram and pentoxifylline on TNF-alpha production and HIV-1
       replication were determined in infected and uninfected peripheral blood
       mononuclear cells (PBMC), in a chronically infected promonocytic cell
       line (U1) and in an acutely infected monocytic cell line (BT4A3.5).
       TNF-alpha was determined by specific radioimmunoassay and HIV-1
       replication was measured by p24 antigen and HIV-1 mRNA production.
       RESULTS: Rolipram inhibited TNF-alpha production in LPS- and phorbol
       myristate acetate (PMA)-stimulated PBMC and in PMA-stimulated U1 cells.
       Rolipram also inhibited HIV-1 replication in the U1 cell line, as well
       as in acutely infected PBMC and BT4A3.5 cells. Depending on the
       experimental conditions, rolipram was 10-600 times more potent, on a
       molar basis, than pentoxifylline. CONCLUSION: Rolipram is a potent
       inhibitor HIV-1 replication and therefore deserves further investigation
       as a potential therapeutic agent in the treatment of HIV-1-infected
       patients.
 DE    Cell Line  Cells, Cultured  Comparative Study  Human  HIV Core Protein
       p24/BIOSYNTHESIS  HIV-1/DRUG EFFECTS/*PHYSIOLOGY  Leukocytes,
       Mononuclear/DRUG EFFECTS/METABOLISM/VIROLOGY
       Lipopolysaccharides/PHARMACOLOGY  Monocytes/DRUG
       EFFECTS/METABOLISM/VIROLOGY  Pentoxifylline/PHARMACOLOGY
       Phosphodiesterase Inhibitors/*PHARMACOLOGY  Pyrrolidinones/*PHARMACOLOGY
       RNA, Viral/BIOSYNTHESIS  Support, U.S. Gov't, P.H.S.
       Tetradecanoylphorbol Acetate/PHARMACOLOGY  Tumor Necrosis
       Factor/*ANTAGONISTS & INHIB/BIOSYNTHESIS  Virus Replication/*DRUG
       EFFECTS  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

