This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Moorman, N. J. Articles by Speck, S. H. Search for Related Content PubMed PubMed Citation Articles by Moorman, N. J. Articles by Speck, S. H.

The Gammaherpesvirus 68 Latency-Associated Nuclear Antigen Homolog Is Critical for the Establishment of Splenic Latency

Division of Microbiology and Immunology and The Center for Emerging Infectious Diseases, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia 30329¹

Received 13 March 2003/ Accepted 27 June 2003

Open reading frame 73 (ORF 73) is conserved among the gamma-2-herpesviruses (rhadinoviruses) and, in Kaposi's sarcoma-associated herpesvirus (KSHV) and herpesvirus saimiri (HVS), has been shown to encode a latency-associated nuclear antigen (LANA). The KSHV and HVS LANAs have also been shown to be required for maintenance of the viral genome as an episome during latency. LANA binds both the viral latency-associated origin of replication and the host cell chromosome, thereby ensuring efficient partitioning of viral genomes to daughter cells during mitosis of a latently infected cell. In gammaherpesvirus 68 (HV68), the role of the LANA homolog in viral infection has not been analyzed. Here we report the construction of a HV68 mutant containing a translation termination codon in the LANA ORF (73.STOP). The 73.STOP mutant virus replicated normally in vitro, in both proliferating and quiescent murine fibroblasts. In addition, there was no difference between wild-type (WT) and 73.STOP virus in the kinetics of induction of lethality in mice lacking B and T cells (Rag 1^-/-) infected with 1,000 PFU of virus. However, compared to WT virus, the 73.STOP mutant exhibited delayed kinetics of replication in the lungs of immunocompetent C57BL/6 mice. In addition, the 73.STOP mutant exhibited a severe defect in the establishment of latency in the spleen of C57BL/6 mice. Increasing the inoculum of 73.STOP virus partially overcame the acute replication defected observed in the lungs at day 4 postinfection but did not ameliorate the severe defect in the establishment of splenic latency. Thus, consistent with its proposed role in replication of the latent viral episome, LANA appears to be a critical determinant in the establishment of HV68 latency in the spleen post-intranasal infection.

This article has been cited by other articles:

• DeZalia, M., Speck, S. H. (2008). Identification of Closely Spaced but Distinct Transcription Initiation Sites for the Murine Gammaherpesvirus 68 Latency-Associated M2 Gene. J. Virol. 82: 7411-7421 [Abstract] [Full Text]  
• Forrest, J. C., Speck, S. H. (2008). Establishment of B-Cell Lines Latently Infected with Reactivation-Competent Murine Gammaherpesvirus 68 Provides Evidence for Viral Alteration of a DNA Damage-Signaling Cascade. J. Virol. 82: 7688-7699 [Abstract] [Full Text]  
• Herskowitz, J. H., Siegel, A. M., Jacoby, M. A., Speck, S. H. (2008). Systematic Mutagenesis of the Murine Gammaherpesvirus 68 M2 Protein Identifies Domains Important for Chronic Infection. J. Virol. 82: 3295-3310 [Abstract] [Full Text]  
• Evans, A. G., Moser, J. M., Krug, L. T., Pozharskaya, V., Mora, A. L., Speck, S. H. (2008). A gammaherpesvirus-secreted activator of V{beta}4+ CD8+ T cells regulates chronic infection and immunopathology. J. Exp. Med. 205: 669-684 [Abstract] [Full Text]  
• Gillet, L., Stevenson, P. G. (2007). Evidence for a Multiprotein Gamma-2 Herpesvirus Entry Complex. J. Virol. 81: 13082-13091 [Abstract] [Full Text]  
• Forrest, J. C., Paden, C. R., Allen, R. D. III, Collins, J., Speck, S. H. (2007). ORF73-Null Murine Gammaherpesvirus 68 Reveals Roles for mLANA and p53 in Virus Replication. J. Virol. 81: 11957-11971 [Abstract] [Full Text]  
• Upton, J. W., Speck, S. H. (2006). Evidence for CDK-Dependent and CDK-Independent Functions of the Murine Gammaherpesvirus 68 v-Cyclin. J. Virol. 80: 11946-11959 [Abstract] [Full Text]  
• Obar, J. J., Fuse, S., Leung, E. K., Bellfy, S. C., Usherwood, E. J. (2006). Gammaherpesvirus persistence alters key CD8 T-cell memory characteristics and enhances antiviral protection.. J. Virol. 80: 8303-8315 [Abstract] [Full Text]  
• Fuse, S., Obar, J. J., Bellfy, S., Leung, E. K., Zhang, W., Usherwood, E. J. (2006). CD80 and CD86 Control Antiviral CD8+ T-Cell Function and Immune Surveillance of Murine Gammaherpesvirus 68.. J. Virol. 80: 9159-9170 [Abstract] [Full Text]  
• Allen, R. D. III, Dickerson, S., Speck, S. H. (2006). Identification of Spliced Gammaherpesvirus 68 LANA and v-Cyclin Transcripts and Analysis of Their Expression In Vivo during Latent Infection. J. Virol. 80: 2055-2062 [Abstract] [Full Text]  
• Moser, J. M., Upton, J. W., Allen, R. D. III, Wilson, C. B., Speck, S. H. (2005). Role of B-Cell Proliferation in the Establishment of Gammaherpesvirus Latency. J. Virol. 79: 9480-9491 [Abstract] [Full Text]  
• Lan, K., Kuppers, D. A., Verma, S. C., Sharma, N., Murakami, M., Robertson, E. S. (2005). Induction of Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen by the Lytic Transactivator RTA: a Novel Mechanism for Establishment of Latency. J. Virol. 79: 7453-7465 [Abstract] [Full Text]  
• Song, M. J., Hwang, S., Wong, W. H., Wu, T.-T., Lee, S., Liao, H.-I, Sun, R. (2005). Identification of viral genes essential for replication of murine {gamma}-herpesvirus 68 using signature-tagged mutagenesis. Proc. Natl. Acad. Sci. USA 102: 3805-3810 [Abstract] [Full Text]  
• Coleman, H. M., Efstathiou, S., Stevenson, P. G. (2005). Transcription of the murine gammaherpesvirus 68 ORF73 from promoters in the viral terminal repeats. J. Gen. Virol. 86: 561-574 [Abstract] [Full Text]  
• Willer, D. O., Speck, S. H. (2005). Establishment and Maintenance of Long-Term Murine Gammaherpesvirus 68 Latency in B Cells in the Absence of CD40. J. Virol. 79: 2891-2899 [Abstract] [Full Text]  
• de Lima, B. D., May, J. S., Marques, S., Simas, J. P., Stevenson, P. G. (2005). Murine gammaherpesvirus 68 bcl-2 homologue contributes to latency establishment in vivo. J. Gen. Virol. 86: 31-40 [Abstract] [Full Text]  
• Simas, J. P., Marques, S., Bridgeman, A., Efstathiou, S., Adler, H. (2004). The M2 gene product of murine gammaherpesvirus 68 is required for efficient colonization of splenic follicles but is not necessary for expansion of latently infected germinal centre B cells. J. Gen. Virol. 85: 2789-2797 [Abstract] [Full Text]  
• Moorman, N. J., Lin, C. Y., Speck, S. H. (2004). Identification of Candidate Gammaherpesvirus 68 Genes Required for Virus Replication by Signature-Tagged Transposon Mutagenesis. J. Virol. 78: 10282-10290 [Abstract] [Full Text]  
• Jia, Q., Wu, T.-T., Liao, H.-I, Chernishof, V., Sun, R. (2004). Murine Gammaherpesvirus 68 Open Reading Frame 31 Is Required for Viral Replication. J. Virol. 78: 6610-6620 [Abstract] [Full Text]  
• Fowler, P., Efstathiou, S. (2004). Vaccine potential of a murine gammaherpesvirus-68 mutant deficient for ORF73. J. Gen. Virol. 85: 609-613 [Abstract] [Full Text]