UCSF

Kaposi's Sarcoma-ssociated Herpesvirus (KSHV), is the most recently discovered human tumor virus, as well as the causative agent of Kaposi's Sarcoma (KS), the most common neoplasm in AIDS patients. As a human pathogen, KSHV has evolved to interact with many cellular signaling pathways, especially those involved in control of infection and inflammation. Primary among these pathways is that which leads to the activation of the transcription factor, Nuclear Factor Kappa B (NFκB). NFκB is a master regulator of the pro-inflammatory transcription program and an integral part of the human body's system of innate immunity. This dissertation explores the interactions of KSHV with the NFκB pathway in terms of both the pathology of the KS lesion, contributing to both the inflammatory microenvironment and the presence of spindle cells, as well as the role played by NFκB in the delicate balance between latency and lytic replication.

KS is an inflammatory lesion induced by infection of endothelial cells with the KSHV. Infected endothelial cells assume an elongated (spindle) shape that is one of the histologic signatures of KS. We found that this spindling phenotype can be attributed to expression of a single viral protein known as vFLIP, a known activator of NFκB. vFLIP expression in spindle cells also induces production of a variety of proinflammatory cytokines and cell surface adhesion proteins that likely contribute to the inflammatory component of KS lesions.

Like all herpesviruses, KSHV can produce either latent or lytic infection. We have examined in detail the effects of NFκB activation and inhibition on KSHV replication. In accord with earlier work, we find that inhibition of NFκB signaling in KSHV infected lymphoma cells is associated with enhanced lytic reactivation of KSHV. Similarly, in KSHV infection of primary endothelial cells, but no other tested cell line, inhibition of NF-κB signaling leads to an increase in lytic replication. However, counter-intuitively, NFκB signaling is strongly and consistently activated in lytically infected cells of all lineages tested. This indicates that the relationship of NFκB activation to latency and lytic reactivation is not uniform, but is dependent on the cellular context.