Bovine Herpes Virus 1 (BHV-1) and Herpes Simplex Virus Type 1 (HSV-1) Promote Survival of Latently Infected Sensory Neurons, in Part by Inhibiting Apoptosis

Abstract

α-Herpesvirinae subfamily members, including herpes simplex virus type 1 (HSV-1) and bovine herpes virus 1 (BHV-1), initiate infection in mucosal surfaces. BHV-1 and HSV-1 enter sensory neurons by cell-cell spread where a burst of viral gene expression occurs. When compared to non-neuronal cells, viral gene expression is quickly extinguished in sensory neurons resulting in neuronal survival and latency. The HSV-1 latency associated transcript (LAT), which is abundantly expressed in latently infected neurons, inhibits apoptosis, viral transcription, and productive infection, and directly or indirectly enhances reactivation from latency in small animal models. Three anti-apoptosis genes can be substituted for LAT, which will restore wild type levels of reactivation from latency to a LAT null mutant virus. Two small non-coding RNAs encoded by LAT possess anti-apoptosis functions in transfected cells. The BHV-1 latency related RNA (LR-RNA), like LAT, is abundantly expressed during latency. The LR-RNA encodes a protein (ORF2) and two microRNAs that are expressed in certain latently infected neurons. Wild-type expression of LR gene products is required for stress-induced reactivation from latency in cattle. ORF2 has anti-apoptosis functions and interacts with certain cellular transcription factors that stimulate viral transcription and productive infection. ORF2 is predicted to promote survival of infected neurons by inhibiting apoptosis and sequestering cellular transcription factors which stimulate productive infection. In addition, the LR encoded microRNAs inhibit viral transcription and apoptosis. In summary, the ability of BHV-1 and HSV-1 to interfere with apoptosis and productive infection in sensory neurons is crucial for the life-long latency-reactivation cycle in their respective hosts.

The serum and glucocorticoid-regulated protein kinases (SGK) stimulate bovine herpesvirus 1 and herpes simplex virus 1 productive infection

“…In keeping with these observations, the synthetic corticosteroid dexamethasone accelerates reactivation from latency in TG neuronal cultures or TG organ cultures prepared from mice latently infected with HSV-1 (Du et al, 2012;Halford et al, 1996). Stress, as a result of food and water deprivation during shipping of cattle, weaning, and/or dramatic weather changes increases corticosteroid levels and the incidence of BoHV-1 reactivation from latency, reviewed by (Jones, 2013(Jones, , 2014. Furthermore, the synthetic corticosteroid dexamethasone initiates BoHV-1 reactivation from latency 100% of the time (Inman et al, 2002;Jones, 1998Jones, , 2003Jones, , 2006Jones et al, 2000;Rock et al, 1992;Sheffy and Davies, 1972;Shimeld et al, 1990).…”

Herpes simplex virus 1 regulates β-catenin expression in TG neurons during the latency-reactivation cycle

“…More than 50% of adults in the United States are latently infected with herpes simplex virus 1 (HSV-1), reviewed in [1][2][3]. HSV-1 infections at the surface of the eye or oral cavity lead to life-long latent infections within sensory neurons of trigeminal ganglia (TG) as well as neurons within the central nervous system [4,5].…”

Activation of cellular metabolism during latent Kaposi's Sarcoma herpesvirus infection

“…Therefore, it is assumed that latency is a fairly quiescent infection with little damage to the host cell. Herpesviruses have evolved to encode functions to keep the latently infected host cell alive [1,2]. While Human alphaherpesviruses establish latency in non-dividing cells, the beta and gamma herpesviruses establish latency in proliferating cells and therefore, they must encode proteins to maintain the viral genome during cell division [3–5].…”