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Journal of Virology, March 2005, p. 2891-2899, Vol. 79, No. 5
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.5.2891-2899.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Establishment and Maintenance of Long-Term Murine Gammaherpesvirus 68 Latency in B Cells in the Absence of CD40

David O. Willer and Samuel H. Speck*

Center for Emerging Infectious Diseases, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia

Received 22 July 2004/ Accepted 12 October 2004

Murine gammaherpesvirus 68 ({gamma}HV68), like Epstein-Barr virus (EBV), establishes a chronic infection in its host by gaining access to the memory B-cell reservoir, where it persists undetected by the host's immune system. EBV encodes a membrane protein, LMP1, that appears to function as a constitutively active CD40 receptor, and is hypothesized to play a central role in EBV-driven differentiation of infected naive B cells to a memory B-cell phenotype. However, it has recently been shown that there is a critical role for CD40-CD40L interaction in B-cell immortalization by EBV (K.-I. Imadome, M. Shirakata, N. Shimizu, S. Nonoyama, and Y. Yamanashi, Proc. Natl. Acad. Sci. USA 100:7836-7840, 2003), indicating that LMP1 does not adequately recapitulate all of the necessary functions of CD40. The role of CD40 receptor expression on B cells for the establishment and maintenance of {gamma}HV68 latency is unclear. Data previously obtained with a competition model, demonstrated that in the face of CD40-sufficient B cells, {gamma}HV68 latency in CD40-deficient B cells waned over time in chimeric mice (I.-J. Kim, E. Flano, D. L. Woodland, F. E. Lund, T. D. Randall, and M. A. Blackman, J. Immunol. 171:886-892, 2003). To further investigate the role of CD40 in {gamma}HV68 latency in vivo, we have characterized the infection of CD40 knockout (CD40–/–) mice. Here we report that, consistent with previous observations, {gamma}HV68 efficiently established a latent infection in B cells of CD40–/– mice. Notably, unlike the infection of normal C57BL/6 mice, significant ex vivo reactivation from splenocytes harvested from infected CD40–/– mice 42 days postinfection was observed. In addition, in contrast to {gamma}HV68 infection of C57BL/6 mice, the frequency of infected naive B cells remained fairly stable over a 3-month period postinfection. Furthermore, a slightly higher frequency of {gamma}HV68 infection was observed in immunoglobulin D (IgD)-negative B cells, which was stably maintained over a period of 3 months postinfection. The presence of virus in IgD-negative B cells indicates that {gamma}HV68 may either directly infect memory B cells present in CD40–/– mice or be capable of driving differentiation of naive CD40–/– B cells. A possible explanation for the apparent discrepancy between the failure of {gamma}HV68 latency to be maintained in CD40-deficient B cells in the presence of CD40-sufficient B cells and the stable maintenance of {gamma}HV68 B-cell latency in CD40–/– mice came from examining virus replication in the lungs of infected CD40–/– mice, where we observed significantly higher levels of virus replication at late times postinfection compared to those in infected C57BL/6 mice. Taken together, these findings are consistent with a model in which chronic virus infection of CD40–/– mice is maintained through virus reactivation in the lungs and reseeding of latency reservoirs.

* Corresponding author. Mailing address: Center for Emerging Infectious Diseases, Yerkes National Primate Research Center, 954 Gatewood Rd. N.E., Atlanta, GA 30329. Phone: (404) 727-7665. Fax: (404) 727-7768. E-mail: sspeck{at}rmy.emory.edu.

Journal of Virology, March 2005, p. 2891-2899, Vol. 79, No. 5
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.5.2891-2899.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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