Confocal microscopy analysis revealed not only an increased fre quency of PPAR expressing cells, but also superior nuclear vs. cytoplasmic localization of PPAR protein in Th1Th17 vs. Th1 cells, suggesting the existence of endogenous ligands triggering PPAR nuclear translocation in Th1Th17 cells upon TCR engagement. Whether PPAR vs. PPAR cells within LCL161? the Th1Th17 and also the Th1 pool are particularly permissive to infection and whether the nuclear localization of PPAR contribute to limiting HIV permissiveness in such cells remains unknown. Future studies are needed to determine the role of PPAR en dogenous ligands in controlling HIV permissiveness in primary cells. Our results demonstrate that PPAR activation pathway controls HIV dissemination by acting on HIV infected cells and also by Inhibitors,Modulators,Libraries preventing new integrative infection.

We found that siRNA against PPAR led to Inhibitors,Modulators,Libraries a significant increase in HIV DNA integration and subsequent viral replication when cells were exposed to wt HIV 24 h after PPAR knock down. Of note, similar results were obtained when cells were exposed to single round VSV G pseudotyped virions that enter cells independently of CD4 and core ceptors. Thus, we provide evidence that PPAR exerts its inhibitory effects post entry and prior HIV DNA in tegration. The activation of the PPAR pathway using the synthetic agonist RGZ upon HIV exposure demonstrated a strong inhibition of HIV replication. Consistent with previous studies on dendritic cells, RGZ did not affect the expression of CD4 and CCR5 thus providing further evidence that PPAR activation interferes with HIV replication at post entry levels.

Treatment with RGZ Inhibitors,Modulators,Libraries induced a complete nuclear translocation of PPAR, and this phenomenon was reversed by simultaneous exposure to Inhibitors,Modulators,Libraries the antagonist T007907. The effects of RGZ on HIV DNA integration was observed at late but not early time points post treatment thus, suggesting that nuclear trans location of PPAR in HIV infected cells limits viral replica tion by regulating directly or indirectly HIV transcription and subsequent HIV dissemination. Unexpectedly, the natural PPAR agonist PGJ2 exerted no effect on HIV replication, in contrast to previous studies on different cell types, suggesting that PGJ2 effects are cell dependent. One potential explanation is related to the fact that PGJ2 exerts PPAR independent effects.

Another explanation may be that Th1Th17 selectively ex press transcripts for hydroxyprostaglandin dehydrogenase 15, an enzyme involved in PGs degradation. Inhibitors,Modulators,Libraries Whether, HPGD degrades exogenous PGJ2 remains unknown. Finally, we observed that RGZ dramatically decreased HIV replication in sorted www.selleckchem.com/products/GDC-0449.html Th1Th17 cells thus demonstrating that PPAR indeed negatively controls the HIV permissiveness program in these cells. The ability of RGZ to control HIV replication in Th1Th17 cells but also in total CD4 T cells is of interest in view of future therapies targeting PPAR nuclear translocation in vivo.