Tegument protein control of latent herpesvirus establishment and animation

Abstract

Herpesviruses are successful pathogens that infect most vertebrates as well as at least one invertebrate species. Six of the eight human herpesviruses are widely distributed in the population. Herpesviral infections persist for the life of the infected host due in large part to the ability of these viruses to enter a non-productive, latent state in which viral gene expression is limited and immune detection and clearance is avoided. Periodically, the virus will reactivate and enter the lytic cycle, producing progeny virus that can spread within or to new hosts. Latency has been classically divided into establishment, maintenance, and reactivation phases. Here we focus on demonstrated and postulated molecular mechanisms leading to the establishment of latency for representative members of each human herpesvirus family. Maintenance and reactivation are also briefly discussed. In particular, the roles that tegument proteins may play during latency are highlighted. Finally, we introduce the term animation to describe the initiation of lytic phase gene expression from a latent herpesvirus genome, and discuss why this step should be separated, both molecularly and theoretically, from reactivation.

Figure 1

Establishment of herpesvirus latency. A. Herpes Simplex Virus Type 1 (HSV-1). Infection of a sensory neuron allows for nuclear entry of viral DNA but not the tegument transactivator VP16. Viral immediate early (IE) genes are silenced. B. Human Cytomegalovirus (HCMV). Infection of a CD34+ hematopoietic progenitor cell allows for nuclear entry of viral DNA but not the tegument transactivator pp71. Viral IE genes are silenced by Daxx and an unidentified (?) trans-dominant, HDAC-independent mechanism. C. Epstein-Barr Virus (EBV). Infection of a memory B cell allows for nuclear entry of viral DNA. Tegument transactivators for EBV are uncharacterized. At least one IE gene (Z) and two early genes (BALF1 and BHRF1) are expressed. Z promotes B cell proliferation and BALF1/BHRF1 inhibit apoptosis, both of which appear to be required for the efficient establishment of latency. Z is unable to fully activate lytic phase gene expression because the viral genome is unmethylated.

Figure 2

Maintenance of herpesvirus latency. A. HSV-1. Viral latency associated transcripts (LAT) encode micro RNAs (miRNA) that suppress the expression of viral IE proteins. Nerve growth factor (NGF) induced signaling also helps maintain latency in vitro. Non-dividing neurons do not require a mechanism to replicate or faithfully partition viral genomes. B. HCMV. The contributions of viral mRNAs/transcripts detected during latency (CTLs, LUNA, UL138, US28, vIL10) to the establishment, maintenance, animation, or reactivation from latency have not been fully characterized. Whether or not latently infected progenitor cells divide or self-renew (arrow with question mark) is not known, thus the need for (or presence of) replication or partition functions is also unclear. C. EBV. The viral EBNA1 protein provides replication and partition functions required to maintain latency in dividing B cells. Different types of EBV latency also express other latent genes whose functions appear to be proliferation induction, apoptosis inhibition and immune evasion. EBER and BART transcripts are also expressed during latency. EBERs inhibit protein kinase R (PKR) to maintain translational proficiency, and BARTs are processed into miRNAs. Viral genome methylation prohibits lytic phase gene expression.

Figure 3

Animation and reactivation of herpesvirus latency. A. HSV-1. Stress signals (lightning bolt) induce the de novo expression of VP16 and its recruitment into the nucleus (likely via HCF) to activate viral IE gene expression. A productive reactivation event follows. B. HCMV. Signals (lightning bolt) induce CD34+ cell differentiation into a dendritic cell, inducing animation and subsequent reactivation through unknown molecular mechanisms. C. EBV. Activation by antigen stimulation of the B cell receptor (BCR) induces B cell differentiation into a plasma cell, inducing animation and subsequent reactivation through unknown molecular mechanisms.