HIV type 1 inhibition by protein kinase C modulatory compounds.
The dichotomous effects of the protein kinase C (PKC) modulatory compounds 12-myristate 13-acetate (PMA), prostratin, and ingenol 3-angelate (I3A) on HIV-1 infection were investigated. PKC modulatory compounds were shown to be potent activators of cells latently infected with HIV-1 (I3A > prostratin). Conversely, PKC modulatory compounds inhibited infection of indicator cells (MAGI) with CXCR4-tropic HIV-1 (PMA > I3A > prostratin), and I3A also inhibited infection with CCR5-tropic virus (AD8-1). Pretreatment with the PKC inhibitors prior to treatment with either I3A or PMA resulted in increased infection, indicating inhibition is PKC mediated. Cell infections suggested that I3A rapidly inhibited the virus from infecting cells at an early point in infection. This observation was supported by the demonstration of inhibition at or before the synthesis of early reverse transcription products, and the inability of these compounds to block vesicular stomatitis virus (VSV) pseudotyped HIV-1 particles. As has already been shown with prostratin, treatment with I3A resulted in down-regulation of the CD4 receptor and CXCR4 coreceptor suggesting that this was a contributor to the infection inhibition. Intriguingly, 48 h pretreatment of unstimulated peripheral blood mononuclear cells (PBMC) prior to infection resulted in abrogation of virus production at concentrations where receptor/ coreceptor levels were not significantly reduced. This result hints at the possibility of inhibition by a PKC modulatory compound of an early pathway of viral entry in PBMC.
Warrilow
David
D
Division of Immunology and Infectious Disease, Queensland Institute of Medical Research, Brisbane, Queensland 4006, Australia.
Gardner
Joy
J
Darnell
Grant A
GA
Suhrbier
Andreas
A
Harrich
David
D
D015704:CD4 Antigens / Q000378:metabolism; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy / Q000517:prevention & control*; D015497:HIV-1 / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology*; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019707:Receptors, Chemokine / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency
D015704:CD4 Antigens; D004224:Diterpenes; D010703:Phorbol Esters; D047428:Protein Kinase Inhibitors; D019707:Receptors, Chemokine; C070999:prostratin; D011493:Protein Kinase C; C008125:ingenol; D013755:Tetradecanoylphorbol Acetate