Abstract
BackgroundSeveral alphaherpesviruses, including herpes simplex virus 1 (HSV-1) and pseudorabies virus (PRV), establish lifelong latency in neurons of the trigeminal ganglion (TG). Although it is thought that efficient establishment of alphaherpesvirus latency is based on a subtle interplay between virus, neurons and the immune system, it is not clear which immune components are of major importance for the establishment of latency.Methodology/Principal FindingsHere, using an in vitro model that enables a natural route of infection, we show that interferon alpha (IFNalpha) has the previously uncharacterized capacity to induce a quiescent HSV-1 and PRV infection in porcine TG neurons that shows strong similarity to in vivo latency. IFNalpha induced a stably suppressed HSV-1 and PRV infection in TG neurons in vitro. Subsequent treatment of neurons containing stably suppressed virus with forskolin resulted in reactivation of both viruses. HSV and PRV latency in vivo is often accompanied by the expression of latency associated transcripts (LATs). Infection of TG neurons with an HSV-1 mutant expressing LacZ under control of the LAT promoter showed activation of the LAT promoter and RT-PCR analysis confirmed that both HSV-1 and PRV express LATs during latency in vitro.Conclusions/SignificanceThese data represent a unique in vitro model of alphaherpesvirus latency and indicate that IFNalpha may be a driving force in promoting efficient latency establishment.
Highlights
Alphaherpesviruses are a subfamily of the herpesviruses containing closely related human and animal pathogens, including human herpes simplex virus 1 (HSV-1) and important animal viruses such as the porcine pseudorabies virus (PRV) and bovine herpesvirus 1 (BoHV-1; respiratory symptoms, abortions, and/or neurological symptoms).Cycles of latency and reactivation arguably constitute the most important and fascinating hallmarks of alphaherpesvirus infections
There is direct and indirect evidence to support the general concept that alphaherpesvirus latency and reactivation is based on a subtle interplay between virus, neurons and the immune system, many questions remain about the immune components that are involved in the establishment of latency [4]
In the current study, using an in vitro two-chamber model that enables a natural route of alphaherpesvirus infection of porcine trigeminal ganglion (TG) neurons [11,12], we report that treatment of TG neurons with IFNalpha is sufficient to induce a quiescent HSV-1 and PRV infection in vitro that shows strong similarities to in vivo latency, thereby providing a novel and unique in vitro model to study HSV/PRV latency and reactivation and suggesting that IFNalpha may represent a key immune component involved in efficient establishment of alphaherpesvirus latency in sensory neurons
Summary
Alphaherpesviruses are a subfamily of the herpesviruses containing closely related human and animal pathogens, including human HSV-1 (cold sores, corneal blindness, and encephalitis) and important animal viruses such as the porcine pseudorabies virus (PRV) and bovine herpesvirus 1 (BoHV-1; respiratory symptoms, abortions, and/or neurological symptoms).Cycles of latency and reactivation arguably constitute the most important and fascinating hallmarks of alphaherpesvirus infections. Alphaherpesviruses generally establish latency in sensory neurons, and neurons of the trigeminal ganglion (TG) are the predominant site of latency for several important alphaherpesviruses, such as HSV-1, PRV, and BoHV-1 [1,2,3]. There is direct and indirect evidence to support the general concept that alphaherpesvirus latency and reactivation is based on a subtle interplay between virus, neurons and the immune system, many questions remain about the immune components that are involved in the establishment of latency [4]. Several alphaherpesviruses, including herpes simplex virus 1 (HSV-1) and pseudorabies virus (PRV), establish lifelong latency in neurons of the trigeminal ganglion (TG). It is thought that efficient establishment of alphaherpesvirus latency is based on a subtle interplay between virus, neurons and the immune system, it is not clear which immune components are of major importance for the establishment of latency
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