The Reactivation Effect Of PR-957 On Latent HIV And Its Mechanism Of Action

Combination antiretroviral therapy(cART),which is considered to effectively suppress HIV virus to a clinically undetectable level and greatly improve the survival rate of HIV-imfected patients and prolong the life-span of patients,still cannot completely eliminate HIV to achieve the cure goal.In addition,an interruption of cART causes the virms to rapidly rebound to its pretreatment levels.The main reason why HIV is difficult to elimination is due to the presence of latent HIV reservoirs.That is to say HIV integrates into host cells in a way of transcriptional silence.Nowadays,"shock and kill" strategy,which means activating and clearing virus,has come to public attention.The strategy aims at purging latent reservoirs by awakening latent HIV to transcriptional activation in integrated host cells using latency reactivating agency.Subsequently,the produced complete viruses are cleared away by killer T lymphocytes in immune system and antivirus agencies,achieving the goal of thoroughly curing HIV.However,none of them can be applied in clinical trials to activate latent HIV.Consequently,finding high efficient and low toxic activators is yet a hot point in curing latent HIV.Immunoproteasome,a special proteasomes,is mainly expressed in hematopoietic cells.In previous studies,proteasome inhibitor was found to activate latent HIV,however,researches on immunoproteasome inhibitors in affecting latent HIV were not reported up to now.Here,we tested the activation activity of PR-957 by a variety of experimental methods and the mechanism of action is discussed preliminarily based on J-Lat 10.6 cells as the main test subject.The results indicated that PR-957 could significantly raise green fluorescent protein(GFP)positive cell percentage in J-Lat 10.6 cells,the HIV's transcription and the expression of p24,HIV capsid protein,were promoted in ACH2 cells,as well.PR-957 also boosts HIV gene expression in PBMCs of chronic infection of patients.Delightedly,PR-957 doesn't influence vitality of the J-Lat10.6,ACH2 and PBMCs.Except for that,it can not only have nothing to cause extensive T cell activation,but also reduce the expression of HIV receptors and co-receptors during its active concentration range.Furthermore,PR-957 has a synergistic activating effect with the classical activators like Prostratin,SAHA and JQ1.Through a further mechanism research,we discovered that the way that PR-957 activates latent HIV is relative to up-regulate p-TEFb expression and activate HSF1 pathway to achieve the goal of promoting HIV transcription.In the last part,in order to explore the combined effect of PR-957 and antiviral drugs,we selected three classic antiviral drugs in this study.In summary,our results indicated that PR-957 was expected as an ideal latent infection activator with clinical application prospects.