?-herpesviruses are closely associated with the development of lymphoproliferative disease and lymphomas, as well as other cancers. Notably, herpesviruses in general are able to establish life-long infections in their natural host(s). The long term goal of this research is to understand how ?-herpesviruses manipulate normal B or T cell development to persist within the lymphoid compartment of the infected host. Understanding the mechanisms used by ?- herpesviruses to persist in the infected host may lead to the development of strategies for interfering with chronic infection. Such therapies would be useful in the management of immunosuppressed individuals (e.g., organ transplant and AIDS patients) who are particularly susceptible to developing ?-herpesvirus-associated tumors. The focus of the proposed studies on murine ?-herpesvirus 68 (MHV68;also referred to as MHV68) represents an ongoing effort to develop a tractable small animal model for characterizing establishment and maintenance of ?-herpesvirus latency within the lymphoid compartment, and to determine the importance of B cell latency in the maintenance of chronic infection.
The specific aims of this renewal application are as follows:
Aim 1. Characterization of MHV68 immortalized murine fetal liver-derived B cell lines: 1.a. Identify stage of B cell differentiation of MHV68 infected FLC-derived B cell lines;1.b. Characterize viral gene expression in MHV68 infected FLC-derived B cell lines;1.c. Determine what viral genes are essential for FLC-derived B cell immortalization;and 1.d. Adoptive transfer of MHV68 infected FLC-derived B cell lines into immunocompetent mice.
Aim 2. Characterization of MHV68 latency programs and viral antigens: 2.a. Identify viral genes expressed in distinct latently infected B cell and macrophage populations; 2.b. Characterize alterations in target cells with viral mutants and altered routes of inoculation;and 2.c. Characterize newly identified latency-associated gene products.
Aim 3. Role of B cells in maintaining chronic MHV68 infection: 3.a. Determine whether MHV68 infects progenitor cells in the bone marrow; 3.b. Characterize latently infected cell types in B cell-deficient (MuMT) mice;and 3.c. Assess consequences of depleting B cells prior to or following MHV68 infection.
?-herpesviruses are able to establish life-long infections in their natural host(s), and are closely associated with the development of lymphoproliferative disease and lymphomas, as well as other cancers. The long term goal of this research is to understand how ?-herpesviruses manipulate normal B or T cell development to persist within the lymphoid compartment of the infected host, as insights in shared mechanisms utilized by this family of viruses may lead to the development of strategies for interfering with chronic infection. In particular, such therapies would be useful in the management of immunosuppressed individuals (e.g., organ transplant and AIDS patients) who are particularly susceptible to developing ?-herpesvirus-associated tumors.
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|Collins, Christopher M; Speck, Samuel H (2012) Tracking murine gammaherpesvirus 68 infection of germinal center B cells in vivo. PLoS One 7:e33230|
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|Krug, Laurie T; Collins, Christopher M; Gargano, Lisa M et al. (2009) NF-kappaB p50 plays distinct roles in the establishment and control of murine gammaherpesvirus 68 latency. J Virol 83:4732-48|
|Collins, Christopher M; Boss, Jeremy M; Speck, Samuel H (2009) Identification of infected B-cell populations by using a recombinant murine gammaherpesvirus 68 expressing a fluorescent protein. J Virol 83:6484-93|
|Herskowitz, Jeremy H; Siegel, Andrea M; Jacoby, Meagan A et al. (2008) Systematic mutagenesis of the murine gammaherpesvirus 68 M2 protein identifies domains important for chronic infection. J Virol 82:3295-310|
|Forrest, J Craig; Speck, Samuel H (2008) Establishment of B-cell lines latently infected with reactivation-competent murine gammaherpesvirus 68 provides evidence for viral alteration of a DNA damage-signaling cascade. J Virol 82:7688-99|
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