Characterisation of the interactions between the KSHV ORF57 protein and the human TREX complex (360G-Wellcome-093788_Z_10_Z)

Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncovirus responsible for the formation of Kaposi's sarcoma (KS). Tumour formation is closely associated with immune suppression1 and shows an epidemic-like morbidity and high mortality in patients with AIDS. Concurrent with the HIV epidemic approximately 17% of the population in Sub-Saharan Africa develop KS. Presently, KS is the most common type of cancer in Africa. The KSHV ORF57 encodes a multifunctional protein essential for virus replication. It recruits the human transcription/export (hTREX) complex to form an export competent viral ribonucleoprotein particle (vRNP), in order to facilitate nuclear export of viral intronless mRNAs. We have recently shown for the first time that CIP29, a newly identified member of the hTREX complex, is also part of the ORF57-mediated vRNP. To date, the role of CIP29 within the hTREX complex remains to be elucidated, although speculations suggest that CIP29 functions as an accessory factor to the DEAD-box helicase UAP56. Understanding the role of CIP29 in both the hTREX complex and the vRNP may have important implications for viral pathogenesis and will aid the development of new treatments. Therefore, this project has the following objectives: 1) Characterisation of the functional significance of the ORF57/CIP29 interaction. 2) Determination if inhibition of ATP-dependent RNA helicase UAP56 using ring expanded nucleosides affects KSHV mRNA export and replication. 3) Elucidation of the role of other putative members in the hTREX complex and their role in ORF57-mediated nuclear export of viral intronless mRNAs.