An increased frequency of Th1 cells in HIV infected subjects may be deleterious given the ability of these cells to produce pro inflammatory cytokines such as TNF. In addition, the finding that Th1 vs. Th1Th17 cells over expressed the CDH1 mRNA, known to inhibit HIV specific kinase inhibitor Trichostatin A CD8 T cell functions via interaction with its receptor KLRG1, suggests a deleterious role of Th1 cells in HIV pathogenesis. In addition to known Th17 specific transcription factors, we demonstrate that Th1Th17 vs. Th1 expressed at superior levels the transcription factors RUNX1, known to mediate the transactivation of RORC ATF5, involved in T cell activation ARTNL, a component of the circadian clock and an HIV dependency factor PPAR and also KLF11, which is a PPAR co regulator and direct transcriptional target.

HIV permissiveness in Th1Th17 cells was also associated with Inhibitors,Modulators,Libraries superior expression of the costimulatory molecules CD28 and CD40LGCD154, molecules involved in the regulation Inhibitors,Modulators,Libraries of apoptosis such as FASLG, and cyto kines such as IL 2 and IL 15. The expression of TGFBR1 TGFBR2 and IL23R on Th1Th17 cells is indicative of their ability to respond to TGF B and IL 23, respectively. TGF B is essential to Th17 differentiation, while IL 23 is involved in the maintenance of the Th17 polari zation and critical for the development of a pathogenic Th17 profile. The expression of genes important for signal transduc tion downstream of the TCR andor cytokine receptors also indicates a greater susceptibility of Th1Th17 cells to activation and a potential contribution to inflammation.

Inhibitors,Modulators,Libraries For example, Th1Th17 cells preferentially express MAP KAPK2MK2, a kinase involved in the production of TNF and IL 6 and MAP3K4, a kinase involved the p38 JNK pathway activation in response to TGF B. Indeed, signaling through p38 is important for HIV replication. In contrast to Th1Th17, Th1 cells expressed Inhibitors,Modulators,Libraries at superior levels several 10 genes of the zinc finger family, including the ZNF382, a tumor suppressor acting via the inhibition of the NF B signaling pathway. Also, Th1 cells preferentially express GRK5 and CNKSR2 KSR2, two molecules that can inhibit the transcriptional activity of NF B. Interestingly, Inhibitors,Modulators,Libraries genome wide siRNA screens for HIV dependency factor identified NF B pathway as being key for HIV permissiveness. It was also shown that the HIV LTR promoters have binding sites for NF B that are important for the transcription of the virus.

It would be of interest to determine whether the expression of kinases GRK5 and CNKSR2 limits NF B translocation in Th1 cells thus, explaining their resistance to HIV infection. One major finding of our study is the identification download the handbook of PPAR as an intrinsic negative regulator of HIV permis siveness in Th1Th17 cells. PPAR is a ligand dependent nuclear receptor that acts as a transcriptional repressor in macrophages and T cells. The localization of PPAR in the nucleus vs.