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Structural, functional, and genetic comparisons of Epstein-Barr virus nuclear antigen 3A, 3B, and 3C homologues encoded by the rhesus lymphocryptovirus.

ABSTRACT: EBNA-3A, -3B, and -3C are three latent infection nuclear proteins important for Epstein-Barr virus (EBV)-induced B-cell immortalization and the immune response to EBV infection. All three are hypothesized to function as transcriptional transactivators, but little is known about their precise mechanism of action or their role in EBV pathogenesis. We have cloned and studied the three EBNA-3 homologues from a closely related lymphocryptovirus (LCV) which naturally infects rhesus monkeys. The rhesus LCV EBNA-3A, -3B, and -3C homologues have 37, 40, and 36% amino acid identity with the EBV genes, respectively. Function, as measured by in vitro assays, also appears to be conserved with the EBV genes, since the rhesus LCV EBNA-3s can interact with the transcription factor RBP-Jkappa and the rhesus LCV EBNA-3C encodes a Q/P-rich domain with transcriptional activation properties. In order to better understand the relationship between these EBV and rhesus LCV latent infection genes, we asked if the rhesus LCV EBNA-3 locus could be recombined into the EBV genome and if it could substitute for the EBV EBNA-3s when assayed for human B-cell immortalization. Recombination between the EBV genome and rhesus LCV DNA was reasonably efficient. However, these studies suggest that the rhesus LCV EBNA-3 locus was not completely interchangeable with the EBV EBNA-3 locus for B-cell immortalization and that at least one determinant of the species restriction for LCV-induced B-cell immortalization maps to the EBNA-3 locus. The overall conservation of EBNA-3 structure and function between EBV and rhesus LCV indicates that rhesus LCV infection of rhesus monkeys can provide an important animal model for studying the role of the EBNA-3 genes in LCV pathogenesis.

SUBMITTER: Jiang H

PROVIDER: S-EPMC112088 | biostudies-literature | 2000 Jul

REPOSITORIES: biostudies-literature

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Structural, functional, and genetic comparisons of Epstein-Barr virus nuclear antigen 3A, 3B, and 3C homologues encoded by the rhesus lymphocryptovirus.

Jiang H H Cho Y G YG Wang F F

Journal of virology 20000701 13

EBNA-3A, -3B, and -3C are three latent infection nuclear proteins important for Epstein-Barr virus (EBV)-induced B-cell immortalization and the immune response to EBV infection. All three are hypothesized to function as transcriptional transactivators, but little is known about their precise mechanism of action or their role in EBV pathogenesis. We have cloned and studied the three EBNA-3 homologues from a closely related lymphocryptovirus (LCV) which naturally infects rhesus monkeys. The rhesus ...[more]

PMID: 10846073

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Project description:UnlabelledPrimary 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.

Dataset Information

Structural, functional, and genetic comparisons of Epstein-Barr virus nuclear antigen 3A, 3B, and 3C homologues encoded by the rhesus lymphocryptovirus.

Publications

Structural, functional, and genetic comparisons of Epstein-Barr virus nuclear antigen 3A, 3B, and 3C homologues encoded by the rhesus lymphocryptovirus.

Similar Datasets

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