Cellular Factors Cyclin T1and Sam68:Roles In The Life Cycle Of Human Immunodeficiency Virus, Type1(HIV-1)

Human Immunodeficiency Virus, type1remains a major threat to human health since its discovery in1983. This virus is a complex retrovirus, with compex replication cycle, high mutation possibility and the capability to destroy human immune system. Up to date, strategies to cure the related disease are still with limited effect. The most applicable strategy is the treatment called HAART, which combines several anti-HIV drugs, targeting mainly the components from the virus, for the treatment.Cellular factors were believed to play critical roles in the life cycle of HIV-1. During the past30years, hundreds of cellular factors were identified to be involved in the process of HIV-1replication; and their functions and mechanisms were fully or partially described by numerous research publications. Among those cellular factors, Cyclin T1was known to mediate the transcriptional trans-activation by HIV-1Tat protein; whereas Sam68was generally believed to serve as a co-transporter during the nuclear export of RRE-containing mRNAs.In one of our recent studies, we identified a splice variant of Cyclin T1, which was named as Cyclin T1b, and reported some of its characterizations in the cell. We found this novel cellular factor has a significant inhibitionary function on HIV-1gene expression. It shares180amino acids with the reported Cyclin T1(Cyclin Tla) in the N terminal region, and its C terminal4amino acids are far different from the546amino acids on the Cyclin Tla. This novel Cyclin T1b could thus interact with CDK9but not with HIV-1Tat, therefore compete with Cyclin Tla for the binding with CDk9during the transcription elongation of HIV-1, leading to the failure of RNA polymerase â…¡ activation on the HIV-1LTR, to inhibit the transcription elongation of HIV-1. These findings on the novel cyclin T1splice variant, no doulbt, have added to the complexity of the cellular regulation on HIV-1replication.In the other study, we demonstrated a novel function, other than facilitating Rev-mediated RRE-containing mRNAs export, of Sam68, which is that, Sam68was able to regulate the gene expression of HIV-1by altering its splicing pattern. And this regulation involves the splice sites D4/A7and D1/A3on the HIV-1pre-mRNA. The possible mechanisms could be its interaction with earlier identified splicing factors ASF/SF2and/or hnRNP K. Collectively, our studies added new knowledge into the understandings of cellular factors, especially for their roles in HIV-1life cycle; and the knowledge reported in this thesis could also provide guides for novel AIDS therapeutic strategies.