Rolipram, a specific type IV phosphodiesterase inhibitor, is a potent inhibitor of HIV-1 replication.
OBJECTIVE
To determine the effects of rolipram, a specific type IV phosphodiesterase inhibitor, on tumor necrosis factor (TNF)-alpha production and HIV-1 replication.


METHODS
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.


CONCLUSIONS
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.
Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA.
J B
JB
Angel
B M
BM
Saget
S P
SP
Walsh
T F
TF
Greten
C A
CA
Dinarello
P R
PR
Skolnik
S
S
Endres
D002460:Cell Line; D002478:Cells, Cultured; D016655:HIV Core Protein p24 / Q000096:biosynthesis; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D010431:Pentoxifylline / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D012367:RNA, Viral / Q000096:biosynthesis; D020889:Rolipram; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects*
D016655:HIV Core Protein p24; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D012367:RNA, Viral; D014409:Tumor Necrosis Factor-alpha; D020889:Rolipram; D013755:Tetradecanoylphorbol Acetate; D010431:Pentoxifylline