scholarly journals Granzymes and Caspase 3 Play Important Roles in Control of Gammaherpesvirus Latency

2004 ◽  
Vol 78 (22) ◽  
pp. 12519-12528 ◽  
Author(s):  
Joy Loh ◽  
Dori A. Thomas ◽  
Paula A. Revell ◽  
Timothy J. Ley ◽  
Herbert W. Virgin
Keyword(s):  
Caspase 3 ◽  
Latent Infection ◽  
Granzyme B ◽  
Critical Role ◽  
Small Animal ◽  
Lymphoid Cells ◽  
Epstein Barr Virus Infection ◽  
Murine Gammaherpesvirus ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACT Gammaherpesviruses can establish lifelong latent infections in lymphoid cells of their hosts despite active antiviral immunity. Identification of the immune mechanisms which regulate gammaherpesvirus latent infection is therefore essential for understanding how gammaherpesviruses persist for the lifetime of their host. Recently, an individual with chronic active Epstein-Barr virus infection was found to have mutations in perforin, and studies using murine gammaherpesvirus 68 (γHV68) as a small-animal model for gammaherpesvirus infection have similarly revealed a critical role for perforin in regulating latent infection. These results suggest involvement of the perforin/granzyme granule exocytosis pathway in immune regulation of gammaherpesvirus latent infection. In this study, we examined γHV68 infection of knockout mice to identify specific molecules within the perforin/granzyme pathway which are essential for regulating gammaherpesvirus latent infection. We show that granzymes A and B and the granzyme B substrate, caspase 3, are important for regulating γHV68 latent infection. Interestingly, we show for the first time that orphan granzymes encoded in the granzyme B gene cluster are also critical for regulating viral infection. The requirement for specific granzymes differs for early versus late forms of latent infection. These data indicate that different granzymes play important and distinct roles in regulating latent gammaherpesvirus infection.

scholarly journals Establishment and Maintenance of Gammaherpesvirus Latency Are Independent of Infective Dose and Route of Infection

2003 ◽  
Vol 77 (13) ◽  
pp. 7696-7701 ◽  
Author(s):  
Scott A. Tibbetts ◽  
Joy Loh ◽  
Victor van Berkel ◽  
James S. McClellan ◽  
Meagan A. Jacoby ◽  
...  
Keyword(s):  
Acute Phase ◽  
Latent Infection ◽  
Ex Vivo ◽  
Latent Infections ◽  
Human Pathogens ◽  
Infectious Dose ◽  
Murine Gammaherpesvirus ◽  
Barr Virus ◽  
Route Of Infection ◽  
Epstein Barr

ABSTRACT Gammaherpesviruses such as Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus are important human pathogens that establish long-term latent infections. Understanding of the initiation and maintenance of latent infections has important implications for the prevention and treatment of gammaherpesvirus-related diseases. Although much is known about gammaherpesvirus pathogenesis, it is unclear how the infectious dose of a virus influences its ability to establish latent infection. To examine the relationship between the infectious dose and gammaherpesvirus latency, we inoculated wild-type mice with 0.01 to 106 PFU of murine gammaherpesvirus 68 (γHV68) and quantitatively measured latency and acute-phase replication. Surprisingly, during latency, the frequencies of ex vivo reactivation were similar over a 107-fold range of doses for i.p. infection and over a 104-fold range of doses for intranasal infection. Further, the frequencies of cells harboring viral genome during latency did not differ substantially over similar dose ranges. Although the kinetics of acute-phase replication were delayed at small doses of virus, the peak titer did not differ significantly between mice infected with a large dose of virus and those infected with a small dose of virus. The results presented here indicate that any initiation of infection leads to substantial acute-phase replication and subsequent establishment of a maximal level of latency. Thus, infections with doses as small as 0.1 PFU of γHV68 result in stable levels of acute-phase replication and latent infection. These results demonstrate that the equilibrium level of establishment of gammaherpesvirus latency is independent of the infectious dose and route of infection.

scholarly journals Murine Gammaherpesvirus 68 Genes both Induce and Suppress Lymphoproliferative Disease

2007 ◽  
Vol 82 (2) ◽  
pp. 1034-1039 ◽  
Author(s):  
Vera L. Tarakanova ◽  
Friederike Kreisel ◽  
Douglas W. White ◽  
Herbert W. Virgin
Keyword(s):  
Lymphoid Hyperplasia ◽  
Lymphoproliferative Disease ◽  
Epstein Barr Virus Infection ◽  
Murine Gammaherpesvirus ◽  
Barr Virus ◽  
Epstein Barr ◽  
Gammaherpesvirus 68 ◽  
Barr Virus Infection ◽  
Immunocompromised Mice ◽  
Murine Gammaherpesvirus 68

ABSTRACT Gammaherpesvirus infection is associated with an increased incidence of lymphoproliferative disease in immunocompromised hosts. Murine gammaherpesvirus 68 (γHV68) infection of BALB β2-microglobulin-deficient (BALB β2m−/−) mice provides an animal model for analysis of the mechanisms responsible for the induction of a lymphoproliferative disease, atypical lymphoid hyperplasia (ALH), that is pathologically similar to posttransplant lymphoproliferative disease associated with Epstein-Barr virus infection. Here we report that the γHV68 v-cyclin and v-bcl-2 genes are required for the efficient induction of γHV68-associated ALH in BALB β2m−/− mice, while the v-GPCR gene is dispensable for ALH induction. In contrast to these findings, deletion of the viral M1 gene enhanced ALH. Thus, γHV68 genes can either inhibit or enhance the induction of lymphoproliferative disease in immunocompromised mice.

Murine gammaherpesvirus-68 infection of mice: A new model for human cerebral Epstein-Barr virus infection

2005 ◽  
Vol 57 (4) ◽  
pp. 600-603 ◽  
Author(s):  
Martin Häusler ◽  
Bernd Sellhaus ◽  
Simone Scheithauer ◽  
Matthias Engler ◽  
Evelyn Alberg ◽  
...  
Keyword(s):  
Virus Infection ◽  
Epstein Barr Virus ◽  
Epstein Barr Virus Infection ◽  
New Model ◽  
Murine Gammaherpesvirus ◽  
Barr Virus ◽  
Epstein Barr ◽  
Gammaherpesvirus 68 ◽  
Barr Virus Infection ◽  
Murine Gammaherpesvirus 68

scholarly journals Inherited CD70 deficiency in humans reveals a critical role for the CD70–CD27 pathway in immunity to Epstein-Barr virus infection

2016 ◽  
Vol 214 (1) ◽  
pp. 73-89 ◽  
Author(s):  
Kazushi Izawa ◽  
Emmanuel Martin ◽  
Claire Soudais ◽  
Julie Bruneau ◽  
David Boutboul ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Critical Role ◽  
Epstein Barr Virus Infection ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
Cell Proliferations

Epstein-Barr virus (EBV) infection in humans is a major trigger of malignant and nonmalignant B cell proliferations. CD27 is a co-stimulatory molecule of T cells, and inherited CD27 deficiency is characterized by high susceptibility to EBV infection, though the underlying pathological mechanisms have not yet been identified. In this study, we report a patient suffering from recurrent EBV-induced B cell proliferations including Hodgkin’s lymphoma because of a deficiency in CD70, the ligand of CD27. We show that EBV-specific T lymphocytes did not expand properly when stimulated with CD70-deficient EBV-infected B cells, whereas expression of CD70 in B cells restored expansion, indicating that CD70 on B cells but not on T cells is required for efficient proliferation of T cells. CD70 was found to be up-regulated on B cells when activated and during EBV infection. The proliferation of T cells triggered by CD70-expressing B cells was dependent on CD27 and CD3 on T cells. Importantly, CD27-deficient T cells failed to proliferate when stimulated with CD70-expressing B cells. Thus, the CD70–CD27 pathway appears to be a crucial component of EBV-specific T cell immunity and more generally for the immune surveillance of B cells and may be a target for immunotherapy of B cell malignancies.

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