Mechanism Of Latent HIV Reactivation By Flavonoid Compound LC431

AIDs is a kind of Immune deficiency syndrome that can cause a high rate of fatality and widely spreading,Which is caused by HIV infection.Highly active antiretroviral therapy was considered a good treatment for HIV,However,although the viral load can be reduced to lower than detection limit by HAART,It cannot fundamentally eradicate the virus.Because virus particles can hide themselves into the"reservoir",Once stopped the HAART treatment,the virus will come back.So,the scientists come up with a new stragedy named "shock&kil",It contains two steps:First,Activator is used to force out the virus of CD4+ T cells,Then with the combination of HAART and immune system to prevent any de novo infections.The transcription of protein-coding genes is performed by RNA Polymerase Ⅱ,and P-TEFb can phosphorylate the C-terminal domain of RNA Pol Ⅱ,together with the negative elongation factor DSIF and NELF,reversing their inhibition effect into positive effect,This phosphorylation is important for stimulating the Pol Ⅱ elongation activity to ensure the synthesis of full-length pre-mRNA.As a general transcription elongation factor,P-TEFb is not only required for cellular genes,but also play an important part in HIV-1 dependent transcription.We want to screen out a class of activators that activate latency HIV by activating transcription from natural compounds to achieve the first step in shock&kill.By screening a variety of natural and synthetic compounds,We found that flavonoid compound show a good activity.Flavonoids is a kind of natural drugs which have many pharmacological effects like low toxicity,antibacterial,anti-inflammatory,hpyerglycemic,oxidation resistance,radioresistance,anti-cancer,anti-tumor effects and it can also enhance the immunity ability,We hope to provide new drug for "shock&kill "stragedy.One flavonoid compound named LC431 has a high rate of activation in HIV lantency,which can activate 44%cells in 5 μM treatment,and its activation effect is in time and dose-dependent manner.What’s more,LC431 synergizes with JQ1 or Prostratin to reactivate latent HIV.With the well established transcriptional regulatory model in our lab,we have found that LC431 can release P-TEFb from its inactive complex 7SK snRNP,However,this part of P-TEFb can neither be recruited into the super elongation complex,nor be recruited by Brd4.In the end,we figure out that LC431 may act as a kind of histone deacetylation inhibitor.It can increase acetylation level of histone H4 K2 and K5,It mainly stimulate HIV in the transcription initiation step through PI3K-AKT pathway.What’s more,LC431 also shows a potent anti-tumor activity.To sum up,This research offers the promise that LC431 may be a potent,relatively nontoxic drug that assist in the elimination of latent reservoir in HIV+patients.