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Journal of Virology, November 2003, p. 11661-11673, Vol. 77, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.21.11661-11673.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

A Locus on Mouse Chromosome 6 That Determines Resistance to Herpes Simplex Virus Also Influences Reactivation, While an Unlinked Locus Augments Resistance of Female Mice

Patric Lundberg,1 Paula Welander,1,2,{dagger} Harry Openshaw,1,2 Christina Nalbandian,1 Carl Edwards,3 Lyle Moldawer,4 and Edouard Cantin1,2*

Departments of Virology,1 Neurology, Beckman Research Institute, City of Hope Medical Center, Duarte, California,2 Amgen Inc., Thousand Oaks, California,3 Department of Surgery, University of Florida, Gainesville, Florida4

Received 18 April 2003/ Accepted 25 July 2003

During studies to determine a role for tumor necrosis factor (TNF) in herpes simplex virus type 1 (HSV-1) infection using TNF receptor null mutant mice, we discovered a genetic locus, closely linked to the TNF p55 receptor (Tnfrsf1a) gene on mouse chromosome 6 (c6), that determines resistance or susceptibility to HSV-1. We named this locus the herpes resistance locus, Hrl, and showed that it also mediates resistance to HSV-2. Hrl has at least two alleles, Hrlr, expressed by resistant strains like C57BL/6 (B6), and Hrls, expressed by susceptible strains like 129S6 (129) and BALB/c. Although Hrl is inherited as an autosomal dominant gene, resistance to HSV-1 is strongly sex biased such that female mice are significantly more resistant than male mice. Analysis of backcrosses between resistant B6 and susceptible 129 mice revealed that a second locus, tentatively named the sex modifier locus, Sml, functions to augment resistance of female mice. Besides determining resistance, Hrl is one of several genes involved in the control of HSV-1 replication in the eye and ganglion. Remarkably, Hrl also affects reactivation of HSV-1, possibly by interaction with some unknown gene(s). We showed that Hrl is distinct from Cmv1, the gene that determines resistance to murine cytomegalovirus, which is encoded in the major NK cell complex just distal of p55 on c6. Hrl has been mapped to a roughly 5-centimorgan interval on c6, and current efforts are focused on obtaining a high-resolution map for Hrl.

* City of Hope Medical Center and Beckman Research Institute, Department of Virology, 1500 E. Duarte Rd., Duarte, CA 91010. Phone: (626) 301-8480. Fax: (626) 301-8852. E-mail: ecantin{at}coh.org.

{dagger} Present address: Department of Microbiology, University of Urbana-Champaign, Urbana, IL 61801.

Journal of Virology, November 2003, p. 11661-11673, Vol. 77, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.21.11661-11673.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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