Mechanisms of Kaposi's sarcoma herpesvirus replication and maintenance during latency

Introduction

Oncogenic viruses are the third most common cause of cancer in humans. Kaposi’s sarcoma herpesvirus (KSHV) is an oncogenic virus that establishes life-long latent infection and can drive tumor development in immunocompromised individuals.

Current Challenges

To date, no definitive treatment against KSHV has been developed, and KSHV-derived cancers are uncurable. Despite the advances in understanding KSHV biology, many key aspects are still obscure, and detailed mechanistic studies are needed for the development of rational targeted therapies.

Mechanisms of KSHV Latency

During latency, KSHV exploits the host cell’s replication and segregation machineries to faithfully copy and transmit its genome during cell division.

Research Gaps

Which cellular proteins contribute to these processes and what mechanisms enable the virus to preserve its genome over time remain poorly dissected.

Proposed Methodology

I will remodel the Xenopus laevis egg extract in vitro system, which has been successfully applied to study eukaryotic replication and chromosome segregation, to incorporate the key components of KSHV maintenance and generate a unique tool to dissect the mechanisms of KSHV latency in a test tube.

Research Objectives

With this innovative system in hand and strong of a previously developed powerful mass-spectrometry workflow for protein identification, my group will overcome the limitations of the current methodologies to answer two main questions:

1. What is the extent of the host’s proteome that contributes to KSHV maintenance?
2. What are the molecular mechanisms that drive faithful segregation of the viral genome?

Expected Outcomes

Corroborated by parallel experiments in KSHV infected cells, these ground-breaking findings will answer long-standing questions on the latency of KSHV, setting a solid base for the development of targeted therapies.

Broader Implications

Furthermore, the newly developed latency system in Xenopus egg extract will emerge as a powerful tool for solving puzzling aspects of the biology of other latently infecting viruses.