Abstract

The aim of this proposal is to define the mechanisms responsible for vaccination against gamma-herpesvirus latency. Understanding these mechanisms will contribute to understanding the fundamentals of immunity to gamma-herpesviruses. Infection with two human gamma-herpesviruses, Epstein-Barr Virus (EBV) and Kaposi's sarcoma associated herpesvirus (KSHV, HHVS), is associated with tumors and lymphoproliferative disease especially in AIDS patients and transplant recipients. The mechanisms of immunity to gamma-herpesviruses are incompletely understood and there are no effective vaccines against these viruses. We have used infection of mice with gamma-HV68 (MHV-68), a virus closely related to EBV and KSHV which infects laboratory mice, to define mechanisms of gamma-herpesvirus pathogenesis and immunity. Surprisingly, subunit vaccination approaches used by several other groups effectively control acute gamma-HV68 infection but fail to prevent long term latency. This proposal is based on a novel observation made in our lab that infection with a reactivation deficient v-cyclin gamma-HV68 mutant virus effectively vaccinates against establishment of latency by wildtype. gamma-HV68. Further studies using a newly developed transgenic mouse model have shown that, while B cells are required for vaccination, antibody is not required. This new model provides us an opportunity to directly evaluate the contributions of immune T cells to vaccination against latency without confounding effects of immune antibody. This proposal will define, through the following Aims, the mechanisms responsible for vaccination against latency, thereby extending our fundamental understanding of how the immune system controls chronic viral infection and disease. The two underlying hypotheses being tested are that latency antigen specific T cells are: (i) required for prevention of the establishment of latency, and (ii) can eliminate latently infected cells.
Aim 1) Determine the role of CD4 and CD8 T cells in vaccination against. HV68 latencyAim 2) Identify latency associated antigens recognized by T cells Aim 3) Test the effects of vaccination with latency associated antigens.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA096511-02
Application #
6616244
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2002-07-23
Project End
2006-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$267,665
Indirect Cost

  Institution

Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

Canny, Susan P; Goel, Gautam; Reese, Tiffany A et al. (2014) Latent gammaherpesvirus 68 infection induces distinct transcriptional changes in different organs. J Virol 88:730-8
Canny, Susan P; Reese, Tiffany A; Johnson, L Steven et al. (2014) Pervasive transcription of a herpesvirus genome generates functionally important RNAs. MBio 5:e01033-13
Reese, T A; Wakeman, B S; Choi, H S et al. (2014) Helminth infection reactivates latent ?-herpesvirus via cytokine competition at a viral promoter. Science 345:573-7
Hwang, Seungmin; Maloney, Nicole S; Bruinsma, Monique W et al. (2012) Nondegradative role of Atg5-Atg12/ Atg16L1 autophagy protein complex in antiviral activity of interferon gamma. Cell Host Microbe 11:397-409
Loh, Joy; Popkin, Daniel L; Droit, Lindsay et al. (2012) Specific mutation of a gammaherpesvirus-expressed antigen in response to CD8 T cell selection in vivo. J Virol 86:2887-93
Herr, Roger A; Wang, Xiaoli; Loh, Joy et al. (2012) Newly discovered viral E3 ligase pK3 induces endoplasmic reticulum-associated degradation of class I major histocompatibility proteins and their membrane-bound chaperones. J Biol Chem 287:14467-79
Loh, Joy; Zhao, Guoyan; Nelson, Christopher A et al. (2011) Identification and sequencing of a novel rodent gammaherpesvirus that establishes acute and latent infection in laboratory mice. J Virol 85:2642-56
Levine, Beth; Mizushima, Noboru; Virgin, Herbert W (2011) Autophagy in immunity and inflammation. Nature 469:323-35
Goodwin, Megan M; Canny, Susan; Steed, Ashley et al. (2010) Murine gammaherpesvirus 68 has evolved gamma interferon and stat1-repressible promoters for the lytic switch gene 50. J Virol 84:3711-7
White, Douglas W; Keppel, Catherine R; Schneider, Stephanie E et al. (2010) Latent herpesvirus infection arms NK cells. Blood 115:4377-83

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