Journal of NeuroVirology, 10: 64–70, 2004 c  2004 Journal of NeuroVirology ISSN: 1355-0284 print / 1538-2443 online DOI: 10.1080/13550280490261716 Short Communication The latency-related gene encoded by bovine herpesvirus 1 can suppress caspase 3 and caspase 9 cleavage during productive infection Gail Henderson, 1 Guey-Chuen Perng, 2 Anthony B Nesburn, 2 Steven L Wechsler, 2 and Clinton Jones 1 1 Department of Veterinary and Biomedical Sciences, University of Nebraska, Lincoln, Lincoln, Nebraska, USA; 2 Department of Ophthalmology, University of California Irvine College of Medicine, Orange, California, USA When the bovine herpesvirus 1 (BHV-1) latency-related (LR) gene is inserted into the latency-associated transcript (LAT) locus of a herpes simplex virus type 1 (HSV-1) LAT deletion mutant, high levels of spontaneous reactivation from latency and enhanced pathogenesis occur. The LR gene, but not LAT, inhibits caspase 3 cleavage during productive infection. Plasmids containing LAT or the LR gene inhibit caspase 3 activation in transiently transfected cells, suggesting productive infection blocks certain antiapoptotic properties of LAT. These studies demonstrate a correlation between the enhanced pathogenic po- tential of CJLAT and the LR gene inhibiting caspase 3 cleavage during produc- tive infection. Journal of NeuroVirology (2004) 10, 64–70. Keywords: apoptosis; bovine herpesvirus 1 (BHV-1) latency related (LR) gene; caspase cleavage Bovine herpesvirus 1 (BHV-1) infections cause a sig- nificant economic loss to the cattle industry. Clini- cal symptoms include abortions, encephalitis, con- junctivitis, respiratory disease, genital disease, and pneumonia (Li et al, 1997; Liu et al, 1996; Nicholson and Thornberry, 1997; Wolf and Green, 1999; Zou et al, 1999). BHV-1 also induces immunosuppres- sion resulting in secondary bacterial infections, bron- chopneumonia, and even death. Infection in cattle is initiated by productive infection on mucosal ep- ithelium. During productive infection, 70 to 80 viral genes are temporally expressed. Like other members of the Alphaherpesvirinae subfamily, BHV-1 estab- lishes and maintains a life long latent infection in sensory ganglionic neurons of its host. The only BHV-1 gene expressed in latently infected neurons is the latency-related (LR) transcript that is Address correspondence to Clinton Jones, Department of Vet- erinary and Biomedical Sciences, University of Nebraska, Lincoln, Fair Street at East Campus Loop, Lincoln, NE 68583-0905, USA. E-mail: cjones@unlnotes.unl.edu This study was supported by the Discovery Fund for Eye Re- search, the Skirball Program in Molecular Ophthalmology, Pub- lic Health Service grants to SW (EY11629, and EY12823) and CJ (1P20RR15635), and USDA grants to CJ (2000-02060, 2002-02450, and 2003-02213). Received 2 July 2003; revised 27 August 2003; accepted 29 August 2003. encoded by the LR gene (Rock et al, 1987). A frac- tion of LR RNA is polyadenylated and alternatively spliced in bovine trigeminal ganglia (TG) (Devireddy and Jones, 1998; Hossain et al, 1995). A LR protein has been identified (Hossain et al, 1995) that asso- ciates with cdk2/cyclin complexes (Jiang et al, 1998). LR gene products inhibit S phase entry (Schang et al, 1996) and interfere with chemically induced apoptosis (Ciacci-Zanella et al, 1999). A stop codon mutation near the beginning of the LR protein–coding sequences interferes with virus shedding from the eye and TG during acute infection of calves. Further- more, the LR mutant does not reactivate from latency following dexamethasone treatment (Inman et al, 2001a, 2002), indicating that the LR gene has sev- eral functions that are required for the latency- reactivation cycle. Herpes simplex virus type 1 (HSV-1) encodes a latency-associated transcript (LAT) that is abun- dantly transcribed during latency and is antisense to ICP0 (Jones, 1998; Rock et al, 1987). LAT expres- sion promotes establishment and reactivation from latency in mouse and rabbit models (Maggioncalda et al, 1996; Perng et al, 1994, 1996, 2000; Sawtell, 1997; Sawtell and Thompson, 1992; Thompson and Sawtell, 1997, 2001). LAT inhibits apoptosis (Ahmed et al, 2002; Inman et al, 2001b; Perng et al, 2000) and decreases expression of other viral genes in