Experimental rhesus lymphocryptovirus infection in immunosuppressed macaques: an animal model for Epstein-Barr virus pathogenesis in the immunosuppressed host

Rivailler, Pierre; Carville, Angela; Kaur, Amitinder; Rao, Pasupuleti Visweswara; Quink, Carol; Kutok, Jeffery L.; Westmoreland, Susan; Klumpp, Sherry A.; Simon, Meredith A.; Aster, Jon C.; Wang, Fred

doi:10.1182/blood-2004-01-0342

Cited by 83 publications

(103 citation statements)

References 30 publications

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“…This virus infects through oral transmission, and causes acute and persistent infection, as well as tumorigenesis in immune suppressed monkeys (Moghaddam et al, 1997;Rivailler et al, 2004). This virus was entirely sequenced and seems collinearly homologous to EBV (Rivailler et al, 2002).…”

Section: Lymphocryptoviruses In Monkeysmentioning

confidence: 99%

“…The difficulty in manipulating the macaque immune system to interrogate the functional relevance of rhLCVspecific immune responses points to the limitation of this in vivo system. Indeed, immune suppression for enhanced tumorigenesis and for the analysis of mutant rhLCVs was mainly achieved by co-infection with simian human immunodeficiency virus (SHIV) (Rivailler et al, 2004;Ohashi et al, 2012), which causes more alterations in the immune system than just immune suppression. Therefore, selective depletion of immune compartments is desirable to dissect the contribution of distinct cellular compartments to the immune control of lymphocryptoviruses.…”

Section: Lymphocryptoviruses In Monkeysmentioning

confidence: 99%

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Animal models of Epstein Barr virus infection

Chatterjee

Leung

Münz

2014

Journal of Immunological Methods

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Epstein Barr virus (EBV) was the first human tumor virus to be identified. Despite 50years of research on this oncogenic virus, no therapeutic or prophylactic vaccine is available against this pathogen. In part, the development of such a vaccine is hampered by the lack of in vivo models for EBV infection and immune control. However, with the advent of mice with reconstituted human immune system components (HIS mice), certain aspects of EBV associated diseases and immune responses can be modeled in vivo. In this review, we will discuss the insights that can be gained from these experiments, and how immune system components can be manipulated to interrogate their function during EBV infection. Finally, we will compare EBV immunobiology in HIS mice to infection by EBV-related viruses in monkeys, and we will outline the strengths and weaknesses of these two in vivo models of EBV infection. Both of these models show great promise as a platform for preclinical EBV vaccine testing. AbstractEpstein Barr virus (EBV) was the first human tumor virus to be identified. Despite 50 years of research on this oncogenic virus, no therapeutic or prophylactic vaccine is available against this pathogen. In part, the development of such a vaccine is hampered by the lack of in vivo models for EBV infection and immune control. However, with the advent of mice with reconstituted human immune system components (HIS mice), certain aspects of EBV associated diseases and immune responses can be modeled in vivo. In this review, we will discuss the insights that can be gained from these experiments, and how immune system components can be manipulated to interrogate their function during EBV infection. Finally, we will compare EBV immunobiology in HIS mice to infection by EBV-related viruses in monkeys, and we will outline the strengths and weaknesses of these two in vivo models of EBV infection. Both of these models show great promise as a platform for preclinical EBV vaccine testing. Chatterjee et al. 3

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Section: Lymphocryptoviruses In Monkeysmentioning

confidence: 99%

Section: Lymphocryptoviruses In Monkeysmentioning

confidence: 99%

Animal models of Epstein Barr virus infection

Chatterjee

Leung

Münz

2014

Journal of Immunological Methods

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“…Macaques harbour CMV and LCV that are similar to their human CMV and EBV counterparts in terms of overall genetic organization, tropism, disease caused during immunosuppression and the immune cells important for control of the viruses (Carville & Mansfield, 2008;Moghaddam et al, 1997;Rivailler et al, 2004;Yue & Barry, 2008). In particular, T-cells are critical for control of both CMV and LCV, and depletion of T-cells due to SIV infection or by T-cell targeting therapeutics leads to loss of immune control and overt disease in macaques (Haustein et al, 2008;Kaur et al, 2002Kaur et al, , 2003Rivailler et al, 2004;Schmidtko et al, 2002). Because T-cells are critical for control of CMV and LCV in both humans and macaques, the macaque may serve as a useful animal model for determining the ability of a therapeutic to impair anti-viral T-cell immunity and, in turn, to increase the risk of virus-associated disease.…”

Section: Introductionmentioning

confidence: 99%

Measuring T-cell responses against LCV and CMV in cynomolgus macaques using ELISPOT: Potential application to non-clinical testing of immunomodulatory therapeutics

Kamperschroer

O’Donnell

Schneider

et al. 2013

Journal of Immunotoxicology

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A number of immunomodulatory therapeutics increase the risk of disease associated with latent herpesviruses such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV), a member of the lymphocryptovirus (LCV) family that infects humans. The diseases associated with loss of immunity to these viruses can have major impacts on patients as well as on the commercial viability of the immunomodulatory therapeutics. In an effort to develop non-clinical methods for measuring effects on anti-viral immunity, we have developed an interferon (IFN)-g enzymelinked immunosorbent spot (ELISPOT) assay to quantify the number of CMV or LCV-reactive Tcells in peripheral blood of cynomolgus macaques. After optimization of various parameters, the IFN-g ELISPOT assay was characterized for specificity, intra-assay, monkey-to-monkey, and longitudinal variability and sensitivity to immunosuppression. The results show that nearly all animals have detectable responses against both CMV and LCV and responses were derived from T-cells specific to the virus of interest. Analyses of variability show assay reproducibility ( 23% CV), and that variability over time in anti-viral responses in individual animals (larger for LCV than for CMV) was $2-fold in most animals over a 3-month time period, which is predicted to allow for detection of drug-induced changes when using group sizes typical of non-clinical studies. In addition, the IFN-g ELISPOT assay was capable of detecting decreases in the numbers of CMV and LCV reactive T-cells induced by immunosuppressive drugs in vitro. This assay may allow for non-clinical assessment of the effects of immunomodulatory therapeutics on anti-viral T-cell immunity in monkeys, and may help determine if therapeutics increase the risk of reactivating latent viral infections.

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“…Similar to EBV infection in humans, rhLCV infection is ubiquitous among rhesus macaques (17), and establishes a life-long asymptomatic persistent infection in B cells associated with periodic reactivation and shedding of virus in oral secretions. Immunosuppression can result in the development of rhLCV-associated B cell lymphomas and epithelial cell lesions similar to oral hairy leukoplakia (18). The ability to reproduce primary infection, persistent infection, and lymphomagenesis after experimental infection of rhLCV naive rhesus macaques provides an animal model system for EBV infection in which the role of cellular immune responses to lytic infection Ags might be experimentally tested (18,19).…”

mentioning

confidence: 99%

The BZLF1 Homolog of an Epstein-Barr-Related γ-Herpesvirus Is a Frequent Target of the CTL Response in Persistently Infected Rhesus Macaques

Fogg

Garry

Awad

et al. 2006

The Journal of Immunology

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Although CD8+ T lymphocytes targeting lytic infection proteins dominate the immune response to acute and persistent EBV infection, their role in immune control of EBV replication is not known. Rhesus lymphocryptovirus (rhLCV) is a γ-herpesvirus closely related to EBV, which establishes persistent infection in rhesus macaques. In this study, we investigated cellular immune responses to the rhLCV BZLF1 (rhBZLF1) homolog in a cohort of rhLCV-seropositive rhesus macaques. rhBZLF1-specific IFN-γ ELISPOT responses ranging between 56 and 3070 spot-forming cells/106 PBMC were detected in 36 of 57 (63%) rhesus macaques and were largely mediated by CD8+ T lymphocytes. The prevalence and magnitude of ELISPOT responses were greater in adult (5–15 years of age) rather than juvenile macaques (<5 years of age), suggesting that rhBZLF1-specific CTL increase over time following early primary infection. A highly immunogenic region in the carboxyl terminus of the rhBZLF1 protein containing overlapping CTL epitopes restricted by Mamu-A*01 and other as yet unidentified MHC class I alleles was identified. The presence of a robust CD8+ T lymphocyte response targeting this lytic infection protein in both rhesus macaques and humans suggests that these CTL may be important for immune control of EBV-related γ-herpesvirus infection. These data underscore the utility of the rhLCV-macaque model for studies of EBV pathogenesis.

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Experimental rhesus lymphocryptovirus infection in immunosuppressed macaques: an animal model for Epstein-Barr virus pathogenesis in the immunosuppressed host

Cited by 83 publications

References 30 publications

Animal models of Epstein Barr virus infection

Animal models of Epstein Barr virus infection

Measuring T-cell responses against LCV and CMV in cynomolgus macaques using ELISPOT: Potential application to non-clinical testing of immunomodulatory therapeutics

The BZLF1 Homolog of an Epstein-Barr-Related γ-Herpesvirus Is a Frequent Target of the CTL Response in Persistently Infected Rhesus Macaques

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