Non-Coding RNAs In Gammaherpesvirus Infection And Disease The outcome of ?HV infection is strongly influenced by host immune control. Nowhere has this been more apparent than in HIV-infected individuals, and their increased propensity to develop malignancy. Two prime examples of this are Kaposis sarcoma and Non-Hodgkin lymphoma, ?HV- associated malignancies identified by the CDC as AIDS-defining illnesses. While these remain significant cancers in many parts of the world, their incidence in HIV-infected individuals has decreased in the era of highly-active antiretroviral therapy (HAART). While HAART has decreased the incidence of certain AIDS-associated neoplasms, individuals on HAART remain at risk for other ?HV-associated malignancies such as primary effusion lymphoma, Burkitt's lymphoma, plasmablastic lymphoma and diffuse large B cell lymphoma. Beyond tumorigenesis, ?HV infection is also associated with inflammatory pathologies in HIV-infected individuals, including AIDS-associated pneumonitis. While AIDS-associated immune suppression is thought to be a major contributor to uncontrolled chronic ?HV infection, it is likely that the immune and inflammatory dysregulation observed in HIV- infected individuals may impact ?HV pathogenesis in as yet undescribed ways. All ?HV analyzed to date express ncRNAs, including miRNAs. These RNAs have a significant potential to modify gene expression without encoding viral proteins that can be recognized and targeted by the immune response..The role of these ncRNAs during in vivo infection and pathogenesis remains unclear. ?HV68 is uniquely well-suited to address these gaps in knowledge, in providing a system that supports virus replication in vitro and allows analysis of the full course f infection in healthy and immune- suppressed hosts. We have studied the viral ncRNAs since our discovery of the gHV68 miRNAs, and we have an extensive set of reagents and expertise to address the function and mechanism of this ncRNAs. In this study, we will determine the effect of a number of ncRNA recombinant viruses in vivo, in healthy and immune deficient individuals. Further, we will determine the host interactors of the ncRNAs, and determine how ?HV infection modulates host ncRNAs and transcription. This investigation is likely to provide a foundation for a new nexus of virus/host interactions that is critical to the ?HVs and to HIV, and is a rich ground for future intervention.
HIV infection and HIV mediated immune suppression is associated with defects in gammaherpesvirus control and subsequent disease, including pneumonia and malignancy. The gammaherpesviruses encode small regulatory RNAs that are highly abundant and are implicated in various functions, including transformation. This proposal will investigate interactions among viral small regulatory RNAs and host proteins during virus infection and in disease models of immune suppression.
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