Murine Model of Gammaherpesvirus Latency

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): The long-term objective of the proposed
research is to define the mechanisms that enable the gamma herpesviruses to
persist indefinitely within their immunocompetent hosts. These mechanisms
underlie the pathogenesis and oncogenic potential associated with these
viruses, particularly in individuals with acquired or inherited
immunodeficiencies. Unfortunately, due to the extreme host restrictions of the
human gamma-herpesviruses Epstein-Barr virus (EBV) and Kaposi's
sarcoma-associated herpesvirus (KSHV), it has not been possible to directly
address the mechanisms responsible for EBV and KSHV persistence in a relevant
host setting. Infection of laboratory mice with the murine gamma-herpesvirus
MHV-68 (closely related to KSHV) offers a highly tractable and potential model
of human gamma-herpesvirus persistence, but viral latency in this system has
not been sufficiently characterized at the molecular level to enable
exploitation of this model for these purposes. Therefore, the immediate goals
of the proposed research are to define the molecular characteristics of MHV-68
latency. To obtain our objective, we propose three specific aims. Under Aim 1
we will define the programs of MHV-68 latency gene expression during the
establishment and maintenance phases of latency within the hematopoietic-cell
reservoirs of latent virus (activated and resting B cells, macrophages, and
dendritic cells). Specifically, we will screen these cells by RT-PCR and
Southern blot hybridization for expression of the MHV-68 latency genes M2, M3,
M1 1, 72, 73 and 74. Additionally, we propose to identify potentially novel
MHV-68 latency genes expressed in these cells that are not apparent from
analysis of the viral genornic DNA sequence. Under Aim 2 we will address the
functions of three latency-associated genes: M2, 73 and 74, for which little or
no information is available. Under Aim 3 we will define the impact of MHV-68
latency on cellular gene expression in vivo at the cellular level. Together,
these specific aims will fill the significant gaps that currently remain in our
knowledge of the latent life cycle of MHV-68, as well as provide better insight
into the mechanisms that the gamma-herpesviruses as a group exploit to maintain
latency, and thus contribute to their pathogenic potential.
StatusFinished
Effective start/end date7/1/016/30/02

Funding

  • National Cancer Institute: $274,199.00

Fingerprint Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.