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Journal of Virology, September 2007, p. 9825-9837, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.00842-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Analysis of Viral cis Elements Conferring Kaposi's Sarcoma-Associated Herpesvirus Episome Partitioning and Maintenance{triangledown}

Rebecca L. Skalsky, Jianhong Hu, and Rolf Renne*

Department of Molecular Genetics and Microbiology and University of Florida Shands Cancer Center, University of Florida, Gainesville, Florida 32610

Received 19 April 2007/ Accepted 29 June 2007

Maintenance of Kaposi's sarcoma-associated herpesvirus (KSHV) episomes in latently infected cells is dependent on the latency-associated nuclear antigen (LANA). LANA binds to the viral terminal repeats (TR), leading to recruitment of cellular origin recognition complex proteins. Additionally, LANA tethers episomes to chromosomes via interactions with histones H2A and H2B (A. J. Barbera et al., Science 311:856-861, 2006). Despite these molecular details, less is known about how episomes are established after de novo infection. To address this, we measured short-term retention rates of green fluorescent protein-expressing replicons in proliferating lymphoid cells. In the absence of antibiotic selection, LANA significantly reduced the loss rate of TR-containing replicons. Additionally, we found that LANA can support long-term stability of KSHV replicons for more than 2 months under nonselective conditions. Analysis of cis elements within TR that confer episome replication and partitioning revealed that these activities can occur independently, and furthermore, both events contribute to episome stability. We found that replication-deficient plasmids containing LANA binding sites (LBS1/2) exhibited measurable retention rates in the presence of LANA. To confirm these observations, we uncoupled KSHV replication and partitioning by constructing hybrid origins containing the Epstein-Barr virus (EBV) dyad symmetry for plasmid replication and KSHV LBS1/2. We demonstrate that multiple LBS1/2 function in a manner analogous to that of the EBV family of repeats by forming an array of LANA binding sites for partitioning of KSHV genomes. Our data suggest that the efficiency with which KSHV establishes latency is dependent on multiple LANA activities, which stabilize viral genomes early after de novo infection.

* Corresponding author. Mailing address: University of Florida, 1613 Mowry Road, Gainesville, FL 32610-3633. Phone: (352) 273-8204. Fax: (352) 273-8299. E-mail: rrenne{at}ufl.edu

{triangledown} Published ahead of print on 11 July 2007.

Journal of Virology, September 2007, p. 9825-9837, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.00842-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Hu, J., Liu, E., Renne, R. (2009). Involvement of SSRP1 in Latent Replication of Kaposi's Sarcoma-Associated Herpesvirus. J. Virol. 83: 11051-11063 [Abstract] [Full Text]  


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