Mechanisms of ERK activation in gammaherpesvirus

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DESCRIPTION (provided by applicant): Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of three human malignancies, including Kaposi's sarcoma (KS), the most common AIDS-related neoplasm worldwide. While the widespread use of HAART therapy has resulted in a decline in the number of KS cases in the US, KS incidence has increased in developing countries where the AIDS epidemic continues. The long-term objective of this study is to broaden our understanding of the basic biology of gammaherpesviruses, including structure, assembly, and virus-host cell interactions. With the recent finding of ERK1/2 within the purified virion of Rhesus monkey rhadinovirus (RRV), a close homolog of KSHV, we began to speculate the importance of this pathway in viral infection. We hypothesize that the incorporation of these enzymes may represent a snapshot of the cellular environment during viral infection, reflecting a cellular pathway that is highly active in the vicinity of viral replication and assembly and that may play important roles during virus production. Two specific aims are proposed to test this hypothesis. The first is designed to determine the structural aspect of ERK1/2 incorporation. We will biochemically confirm mass spectrometry data, while also determining structural localization, species-specificity, and approximate abundance of these species within the particle. The second is to define the interaction between RRV and the MEK/ERK pathway during de novo infection. We will determine the kinetics of ERK activation, as well as define a mechanism for late phase activation. With the use of viral DNA replication inhibitors, as well as global transcription and translation inhibitors, we will assess role of potential viral gene (s) and cellular processes in activating ERK during RRV infection. Relevance to public health: Viruses, having evolved with the host, have found ways to manipulate the cellular environment for their benefit. This project is designed to provide insight into how gammaherpesviruses interact with and use the MEK/ERK pathway during viral infection. Due to the weakened immune system of AIDS patients, KS treatment is often limited; however, our studies may identify virus and cancer cell specific markers that may become targeted therapies for KS. This approach may enable us to interfere with infection and subsequent disease progression, even in the absence of a healthy immune system.