Effects And Mechanism Of HMBA And Prostratin On HIV-1 Transcription

Through the HIV epidemic of over 20 years,people have strived to find cures for AIDS.The introduction of highly active antiretroviral therapy(HAART) has dramatically reduced the fatality rate of infected patients.After antiretroviral therapy, HIV-RNA drop to undetectable levels in the blood of most patients.However,the virus cannot be eradicated.In resting CD4 T-lymphocytes,provirus has potential of replication,at undetectable levels.Therefore resting CD4 T-lymphocytes act as a reservoir for HIV virus.Current methods explore ways to activate viral expression, and eradicate the virus through recognition by the immune system.Recently,drugs HMBA and protratin have shed new light on HIV therapy,as they can activate latently infected HIV-1.HMBA is a hybrid bipolar compound that effectively induces cell differentiation and retards cell growth.Prostratin,found in the bark of the mamala tree,can also induce HIV resistance under laboratory conditions.In this thesis,using drug treatment of stable cell line and transient transfected HeLa cell models,we observed activation of HIV-LTR transcription by HMBA and prostratin.Our work on deletion mutants of the HIV-LTR-luciferase reporter gene showed that binding sites of the transcriptional factor Spl are essential for HIV-LTR response to HMBA,and NF-κB binding sites are required for activation by prostratin. We further discovered that prostratin activates protein kinase D3(PKD3) through the PKC pathway,to activate HIV-1 transcription.