Herpes Simplex Virus Type 1 Latently Infected Neurons Differentially Express Latency-Associated and ICP0 Transcripts

Abstract

Herpes simplex virus type 1 (HSV-1) is a human neurotropic virus, which establishes lifelong latent infection. During the acute phase of infection, viral replication is characterized by the expression of immediate early (IE), early, and late genes in an ordered cascade that leads to the release of infectious particles that can attach to nerve endings. Following axonal transport to neuronal cell bodies, HSV-1 can either replicate or persist in a latent state in the infected host (62).During latency infectious virus cannot be detected in neuronal tissues (62). The viral genome is circularized, complexed with histones, and maintained in a repressed state with the exception of the latency-associated transcripts (LATs) that are encoded within the repeats flanking the unique long region of the HSV-1 genome (12, 33, 60). The LATs (2 kb and 1.5 kb in size) are stable unpolyadenylated introns that are retained within the nuclei of latently infected neurons (reviewed in references 33 and 56) and are spliced from a primary 8.3-kb transcript (19). Their unusual stability has been related to modifications in the consensus sequences of splicing (84), resulting in an unstable 6.3-kb spliced exon (13, 85) and a stable 2-kb LAT intron that is expressed during both acute and latent infections (73,84). During latent neuronal infection, the 2-kb LAT may undergo subsequent splicing that results in a 1.5-kb LAT (1,46,70). The functions of LATs are not yet clearly understood, but mutational analyses and transfection assays of LATs strongly suggest that they have a key role in establishment of latency and/or viral reactivation (29,31,53,64,71,77), besides their antiapoptotic, anti-interferon, and proneuronal survival properties (24,32,52,54,55,78).Several studies failed to detect lytic viral gene expression during HSV-1 latency (20,33). However, some studies reported the detection of transcripts from genes encoding the immediate-early viral protein ICP4 and the early viral protein thymidine kinase (TK) in latently infected trigeminal ganglion (TG) neurons (9, 34). This observation was initially interpreted as a possible result of spontaneous reactivation (33). Since the gene encoding the ICP0 protein of HSV-1 is contained entirely within the region of the HSV-1 genome encoding LATs (reviewed in reference 3), it might be transcribed during latency, as recently reported by Chen et al. for latently infected TG neurons (10). ICP0 is the first viral protein produced during the productive cycle and is thus classically considered a relevant indicator of early-stage reactivation (18,59,65). It nonspecifically transactivates both viral and cellular promoters (18,25,42) and plays a crucial role in the initiation of productive infection following low-multiplicity infections of cells in culture (7,8,17,63). ICP0 is able to initiate both viral gene expression from quiescent genomes in cells in culture and viral reactivation from latently infected sensory neurons in vivo (6, 26, 27,

Herpes Simplex Virus 1 Infection of Tree Shrews Differs from That of Mice in the Severity of Acute Infection and Viral Transcription in the Peripheral Nervous System

“…We subsequently conducted immunofluorescence staining with ICP0 monoclonal antibodies, but did not detect any ICP0 protein in acutely infected TGs either in mice or in tree shrews (data not shown). This result is supported by the earlier study of Chen et al, in which they observed ICP0 transcripts but no ICP0 protein in primary neuron cultures (39) and the studies of Mailett et al, who studied ICP0 expression in an oro-ocular model of HSV infection and noted ICP0 transcripts in the nuclei of some neuronal cells during latency (38). The level of ICP0 transcript will be further investigated later in this study.…”

“…8H). Although we could hardly detect ICP0 transcript in mouse latently infected TGs, ICP0 transcript has been detected during latency in mice by others (38); nonetheless, both in situ hybridization results discussed here and qRT-PCR results shown in Fig. 6 strongly suggest that latently infected tree shrew TGs express much higher levels of ICP0 transcript than mouse TGs during HSV-1 latency.…”

“…The trend of high levels of both LAT transcripts in tree shrew TGs continued at 20 and 33 days p.i., suggesting that, at this stage, HSV-1 in tree shrew TG exhibited latent infection. The robust levels of ICP0 transcript, however, is in contrast to HSV-1 latency seen in mice and rabbits, where ICP0 transcript is very low (38). Considering that we did not detect any HSV-1 antigens in tree shrew TGs (Fig.…”

HSV-1 gene expression from reactivated ganglia is disordered and concurrent with suppression of latency-associated transcript and miRNAs

“…Evidence that expression of LATs and expression of ICP0 gene may be incompatible was reported by Amelio et al (16) and Maillet et al (17). The studies with actinomycin D and cycloheximide suggest that these two events are linked.…”

Promyelocytic Leukemia-Nuclear Body Proteins: Herpesvirus Enemies, Accomplices, or Both?

“…The exogenous expression of ICP0 or pp71 can activate gene expression from quiescent HSV-1 genomes [98][99][100][101]. Furthermore, latently-infected cells express antisense transcripts that may affect the expression of ICP0 [102][103][104][105] or pp71 [106], implying that repressing the expression of these proteins may be important for the maintenance of the latent state. For HSV-1, chromatin remodeling to achieve or maintain viral genome silencing also seems to occur through additional processes independent of PML-NB proteins [107].…”