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.