Coinfection and reactivation by KSHV, EBV and HCMV are important opportunistic complications that affect immunosuppressed AIDS patients. In particular the spread of HIV throughout Africa into populations that already had high levels of asymptomatic KSHV infections has led to the emergence of Kaposi's Sarcoma (KS) as the most prevalent of all human cancers in Southern Africa. Establishment of a latent-state infection by KSHV drives the proliferation and immortalization of both B-lymphocytes and vascular endothelial cells by mechanisms that are very different from the well-known paradigms for latent transformation of B-cells by EBV. In particular, the lytic cycle program of KSHV is also critical both for maintenance and spread of infection in vivo, as well as through prolonged expression of the """"""""captured"""""""" early lytic """"""""pathogenic genes"""""""", and provides an effective target for therapy as illustrated by the considerable reduction of KS in AIDS patients in the USA who receive anti-herpesvirus therapies. Whilst it used to be thought that cellular functions were essentially all """"""""turned-off"""""""", during the herpesvirus lytic cycle, recent evidence has revealed that the situation is actually much more subtle and involves complex interactions between viral and cellular transcription regulatory factors, not only to effect the trigger into the lytic cycle itself, but also to cause cell cycle arrest and to sustain progression of the full lytic cycle program. ? ? Our recent studies have discovered a previously unsuspected role of two KSHV viral transcription regulators RTA(ORF50) and RAP(K8) in controlling the stability of several key cellular transcription and cell cycle regulatory proteins, particularly the tumor suppressor C/EBP1. These studies have led to a model in which we envisage that a key part of the KSHV (and EBV) switch from latent to lytic infection involves a self- reinforcing positive regulatory loop between C/EBP1 and these viral proteins, leading to high levels of both, followed by sustained activation of downstream viral promoters, G1/S cell cycle arrest, and activation of viral lytic DNA replication. The levels of p21, cJUN and pRB but not E2F1, are also highly augmented during the KSHV lytic cycle and like C/EBP1 they may similarly behave as """"""""honorary viral"""""""" genes. All of these cellular proteins are tumor suppressors or oncogenes that regulate proliferation, growth control, differentiation, senescence and/or apoptosis, and whose functions are mutated or dysregulated in many types of cancer cells. We now plan to focus here on how the viral regulators interact with and control the stability, half-life and function of these key cellular proteins to counteract the established stable latent state in KSHV infected cells. Because of the importance of these cellular regulatory factors, our studies may have an impact that goes beyond just this novel paradigm for sustaining the gamma herpesvirus latent-to-lytic cycle switch.
This is a competitive 5-yr proposal for continuation of funding on a Research Project targeting the viral:cell interaction mechanisms that enable human Kaposi's sarcoma herpesvirus to infect B-cells and endothelial cells leading to Lymphomas and Kaposi's sarcoma, especially in AIDS patients. ? ? ? ? ? ? ?
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