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

Abstract

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.Hrlhas at least two alleles,Hrl^r, expressed by resistant strains like C57BL/6 (B6), andHrl^s, expressed by susceptible strains like 129S6 (129) and BALB/c. AlthoughHrlis 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,Hrlis one of several genes involved in the control of HSV-1 replication in the eye and ganglion. Remarkably,Hrlalso affects reactivation of HSV-1, possibly by interaction with some unknown gene(s). We showed thatHrlis distinct fromCmv1, the gene that determines resistance to murine cytomegalovirus, which is encoded in the major NK cell complex just distal of p55 on c6.Hrlhas been mapped to a roughly 5-centimorgan interval on c6, and current efforts are focused on obtaining a high-resolution map forHrl.