Gammaherpesviruses are ubiquitous persistent pathogens that infect a substantial majority of the world's population. Infection does not have deleterious consequences in most healthy individuals, due to the presence of a potent immune response that contains the infection. In AIDS patients and others with suppressed immune systems, breakdown in immune surveillance can be accompanied by life-threatening gammaherpesvirus-associated disease. There is a pressing need to understand the mechanism by which the immune response, particularly the CD8 T cell response, maintains optimal control of the infection. Our previous work, using the murine gammaherpesvirus model system, clearly indicates that the differentiation state of memory CD8 T cells is a key determinant to maintain benign levels of persistent virus. Memory T cells can be categorized into two types - effector memory T cells (TEM), with the capacity for immediate effector function but limited proliferation, and central memory T cells (TCM) with delayed effector function but the capacity for extensive proliferation. TEM predominate in persistent infections, and are likely critical for surveillance o the virus. However the factors that determine cell fate toward TEM or TCM lineage are currently obscure. We have recently discovered that CD8 cells lacking a key microRNA fail to differentiate appropriately into effector cells, instead skewing toward the memory phenotype. These cells differentiate poorly into long-lived memory cells, and have a marked skewing towards TCM, whereas wild type cells predominantly assume the TEM phenotype. This is important because it indicates a pivotal role for this microRNA in immune surveillance to MHV-68. In addition, factors controlling TCM differentiation are very actively sought, as the generation of these cells is the 'holy grail'of vaccine design against many infectious agents and tumors. This presents a unique opportunity to determine the functional role for microRNA regulation of antiviral CD8 T cell responses. In this proposal we address three hypotheses: (i) During the acute phase of the infection, there is a deficit in the production of short-lived effector CD8 cells, but the generatin of memory precursor cells is intact. (ii) TEM fail to form correctly but differentiation to TCM is intact. (iii) Control of MHV-68 infection is defective in the absence of microRNA, for two reasons. Firstly the T cell response is unable to control the infection. Secondly B cell colonization by latent MHV-68 is altered in the absence of microRNA. Our knowledge of the functions of microRNAs increases each year, as do the tools that enable us to manipulate their activity. Therefore the major impact of this work will be to illuminate the roles of microRNA in the antivira immune response, which have the potential to be manipulated to affect better control of medically important pathogens such as the gammaherpesviruses.

Public Health Relevance

The key event that converts benign persistent infection with the gammaherpesviruses into potentially life threatening disease is the lack of effective immune surveillance. Erosion of immune surveillance in AIDS patients results in a spectrum of different gammaherpesvirus related disease. Our research has the goal of understanding immune surveillance to the gammaherpesviruses. Understanding this process in sufficient detail will enable us to develop better immune therapies

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI069943-07
Application #
8660592
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Beisel, Christopher E
Project Start
2006-04-01
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Dartmouth College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Hanover
State
NH
Country
United States
Zip Code
03755
Hu, Zhuting; Molloy, Michael J; Usherwood, Edward J (2016) CD4(+) T-cell dependence of primary CD8(+) T-cell response against vaccinia virus depends upon route of infection and viral dose. Cell Mol Immunol 13:82-93
Hu, Zhuting; Blackman, Marcia A; Kaye, Kenneth M et al. (2015) Functional heterogeneity in the CD4+ T cell response to murine γ-herpesvirus 68. J Immunol 194:2746-56
Gui, Jingang; Hu, Zhuting; Tsai, Ching-Yi et al. (2015) MCL1 enhances the survival of CD8+ memory T Cells after viral infection. J Virol 89:2405-14
Hu, Zhuting; Usherwood, Edward J (2014) Immune escape of γ-herpesviruses from adaptive immunity. Rev Med Virol 24:365-78
Hu, Zhuting; Zhang, Weijun; Usherwood, Edward J (2013) Regulatory CD8+ T cells associated with erosion of immune surveillance in persistent virus infection suppress in vitro and have a reversible proliferative defect. J Immunol 191:312-22
Allie, S Rameeza; Zhang, Weijun; Tsai, Ching-Yi et al. (2013) Critical role for all-trans retinoic acid for optimal effector and effector memory CD8 T cell differentiation. J Immunol 190:2178-87
Liang, Xiaozhan; Crepeau, Rebecca L; Zhang, Weijun et al. (2013) CD4 and CD8 T cells directly recognize murine gammaherpesvirus 68-immortalized cells and prevent tumor outgrowth. J Virol 87:6051-4
Fuse, Shinichiro; Tsai, Ching-Yi; Rommereim, Leah M et al. (2011) Differential requirements for CD80/86-CD28 costimulation in primary and memory CD4 T cell responses to vaccinia virus. Cell Immunol 266:130-4
Allie, S Rameeza; Zhang, Weijun; Fuse, Shinchiro et al. (2011) Programmed death 1 regulates development of central memory CD8 T cells after acute viral infection. J Immunol 186:6280-6
Molloy, Michael J; Zhang, Weijun; Usherwood, Edward J (2011) Suppressive CD8+ T cells arise in the absence of CD4 help and compromise control of persistent virus. J Immunol 186:6218-26

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