Complete Nucleotide Sequence of the Rhesus Lymphocryptovirus: Genetic Validation for an Epstein-Barr Virus Animal Model

Rivailler, Pierre; Jiang, Hua; Cho, Young-gyu; Quink, Carol; Wang, Fred

doi:10.1128/jvi.76.1.421-426.2002

Cited by 119 publications

(117 citation statements)

References 36 publications

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“…In EBV, J plays a central role in regulating expression of all the latent promoters: for the six EBNAs (Cp), LMP-1, and LMP-2, and the J-binding sites within these promoters are conserved in the corresponding promoters within the BaLCV and RhLCV genomes (10,12,43). Furthermore, both RhLCV and BaLCV EBNA-2 homologues bind to J (32,39).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Regulatory Properties of Epstein-Barr Virus Nuclear Antigen 3C Are Conserved in Simian Lymphocryptoviruses

Dalbiès-Tran

Jiang

Ruf

et al. 2003

J Virol

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Epstein-Barr virus (EBV) nuclear antigen 3C (EBNA-3C) is a large transcriptional regulator essential for EBV-mediated immortalization of B lymphocytes. We previously identified interactions between EBNA-3C and two cellular transcription factors, J and Spi proteins, through which EBNA-3C regulates transcription. To better understand the contribution of these interactions to EBNA-3C function and EBV latency, we examined whether they are conserved in the homologous proteins of nonhuman primate lymphocryptoviruses (LCVs), which bear a strong genetic and biological similarity to EBV. The homologue of EBNA-3C encoded by the LCV that infects baboons (BaLCV) was found to be only 35% identical in sequence to its EBV counterpart. Of particular significance, this homology localized predominantly to the N-terminal half of the molecule, which encompasses the domains in EBNA-3C that interact with J and Spi proteins. Like EBNA-3C, both BaLCV and rhesus macaque LCV (RhLCV) 3C proteins bound to J and repressed transcription mediated by EBNA-2 through its interaction with J. Both nonhuman primate 3C proteins were also able to activate transcription mediated by the Spi proteins in the presence of EBNA-2. Like EBNA-3C, a domain encompassing the putative basic leucine zipper motif of the BaLCV-3C protein directly interacted with both Spi-1 and Spi-B. Surprisingly, a recently identified motif in EBNA-3C that mediates repression was not identifiable in the BaLCV-3C protein.Finally, although the C terminus of BaLCV-3C bears minimal homology to EBNA-3C, it nonetheless contains a C-terminal domain rich in glutamine and proline that was able to function as a potent transcriptional activation domain, as does the C terminus of EBNA-3C. The conservation of these functional motifs despite poor overall homology among the LCV 3C proteins strongly suggests that the interactions of EBNA-3C with J and Spi do indeed play significant roles in the life cycle of EBV.Studies using recombinant Epstein-Barr virus (EBV) genomes have identified six latent infection proteins that are essential for EBV-mediated immortalization of B lymphocytes in vitro: EBV nuclear antigen 1 (EBNA-1), EBNA-2, EBNA-LP, EBNA-3A, EBNA-3C, and latent membrane protein (LMP) 1 (5,17,27,29,34,53). Two of these viral proteins, and perhaps the least well understood, are members of the EBNA-3 family of transcriptional regulators. Although the three EBNA-3 genes (3A, 3B, and 3C) share a similar gene structure and are likely to have evolved from a common ancestral gene, the encoded proteins are highly divergent in amino acid sequence. The EBNA-3 proteins are also likely to have diverged functionally, since EBNA-3A and EBNA-3C, but not EBNA-3B, are essential for EBV-mediated immortalization of B lymphocytes. Despite their differences, all EBNA-3 proteins function as transcriptional regulatory proteins whose transcriptional effects are mediated through interactions with cellular sequence-specific DNA-binding proteins, rather than by binding directly to DNA (26,45,50,57,58). In addition to...

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Section: Discussionmentioning

confidence: 99%

Transcriptional Regulatory Properties of Epstein-Barr Virus Nuclear Antigen 3C Are Conserved in Simian Lymphocryptoviruses

Dalbiès-Tran

Jiang

Ruf

et al. 2003

J Virol

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“…A B cell immortalizing ␥-herpesvirus (Cercopithicine herpesvirus 15, rhesus lymphocryptovirus (rhLCV)) homologous to EBV at both the genomic and protein level (15) naturally infects rhesus macaques (16). 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.…”

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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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“…One might predict the host range restriction would be linked to the viral genes most divergent between EBV and rhLCV, i.e., those encoding gp350 (49% amino acid similarity) and the latent infection proteins essential for B cell immortalization (29 to 57% amino acid similarity) (34). Our current experiments formally demonstrate that EBV gp350 and rhLCV gp350 are functionally equivalent for infection of rhesus macaque B cells in vitro and that rhLCV can use EBV gp350 to penetrate the oral mucosa and establish persistent infection in rhesus macaques.…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus gp350 Can Functionally Replace the Rhesus Lymphocryptovirus Major Membrane Glycoprotein and Does Not Restrict Infection of Rhesus Macaques

Herrman

Mühe

Quink

et al. 2016

J Virol

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Primary Epstein-Barr virus (EBV) infection is the most common cause of infectious mononucleosis, and persistent infection is associated with multiple cancers. EBV vaccine development has focused on the major membrane glycoprotein, gp350, since it is the major target for antibodies that neutralize infection of B cells. However, EBV has tropism for both B cells and epithelial cells, and it is unknown whether serum neutralizing antibodies against B cell infection will provide sufficient protection against virus infection initiated at the oral mucosa. This could be stringently tested by passive antibody transfer and oral virus challenge in the rhesus macaque model for EBV infection. However, only neutralizing monoclonal antibodies (MAbs) against EBV are available, and EBV is unable to infect rhesus macaques because of a host range restriction with an unknown mechanism. We cloned the prototypic EBV-neutralizing antibody, 72A1, and found that recombinant 72A1 did not neutralize rhesus lymphocryptovirus (rhLCV) infection of macaque B cells. Therefore, we constructed a chimeric rhLCV in which the native major membrane glycoprotein was replaced with EBV gp350. This chimeric rhLCV became sensitive to neutralization by the 72A1 MAb, efficiently immortalized macaque B cells in vitro, and successfully established acute and persistent infection after oral inoculation of rhesus macaques. Thus, EBV gp350 can functionally replace rhLCV gp350 and does not restrict rhLCV infection in vitro or in vivo. The chimeric rhLCV enables direct use of an EBV-specific MAb to investigate the effects of serum neutralizing antibodies against B cell infection on oral viral challenge in rhesus macaques. IMPORTANCEThis study asked whether the EBV major membrane glycoprotein could functionally replace the rhLCV major membrane glycoprotein. We found that an rhLCV humanized with EBV gp350 is capable of efficiently immortalizing monkey B cells in vitro and reproduces acute and persistent infection after oral inoculation of macaques. These results advance our understanding of why EBV cannot infect rhesus macaques by proving that viral attachment through gp350 is not the mechanism for EBV host range restriction. Humanization of rhLCV with EBV gp350 also confers susceptibility to a potent EBV-neutralizing MAb and provides a novel and significant enhancement to the rhesus macaque animal model where both the clinical utility and biological role of neutralizing MAbs against B cell or epithelial cell infection can now be directly tested in the most accurate animal model for EBV infection. P rimary Epstein-Barr virus (EBV) infection is the most common cause of infectious mononucleosis (IM), and persistentEBV infection is associated with cancers of B cell origin, e.g., Burkitt lymphoma and Hodgkin lymphoma, as well as epithelial cell origin, e.g., nasopharyngeal carcinoma and gastric carcinoma. A vaccine that prevents EBV-associated diseases would provide significant public health benefits (1).The major membrane glycoprotein gp350 is considered an attr...

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Complete Nucleotide Sequence of the Rhesus Lymphocryptovirus: Genetic Validation for an Epstein-Barr Virus Animal Model

Cited by 119 publications

References 36 publications

Transcriptional Regulatory Properties of Epstein-Barr Virus Nuclear Antigen 3C Are Conserved in Simian Lymphocryptoviruses

Transcriptional Regulatory Properties of Epstein-Barr Virus Nuclear Antigen 3C Are Conserved in Simian Lymphocryptoviruses

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

Epstein-Barr Virus gp350 Can Functionally Replace the Rhesus Lymphocryptovirus Major Membrane Glycoprotein and Does Not Restrict Infection of Rhesus Macaques

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