scholarly journals 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

2013 ◽  
Vol 6 ◽  
pp. JCD.S10803 ◽  
Author(s):  
Clinton Jones
Keyword(s):  
Sensory Neurons ◽  
Viral Gene Expression ◽  
Productive Infection ◽  
Viral Gene ◽  
Viral Transcription ◽  
Latently Infected ◽  
Simplex Virus ◽  
Cellular Transcription ◽  
Hsv 1

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.

scholarly journals Cd8+ T Cells Can Block Herpes Simplex Virus Type 1 (HSV-1) Reactivation from Latency in Sensory Neurons

2000 ◽  
Vol 191 (9) ◽  
pp. 1459-1466 ◽  
Author(s):  
Ting Liu ◽  
Kamal M. Khanna ◽  
XiaoPing Chen ◽  
David J. Fink ◽  
Robert L. Hendricks
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Sensory Neurons ◽  
Cd8 T Cells ◽  
Early Proteins ◽  
Latently Infected ◽  
Simplex Virus ◽  
Hsv 1

Recurrent herpes simplex virus type 1 (HSV-1) disease usually results from reactivation of latent virus in sensory neurons and transmission to peripheral sites. Therefore, defining the mechanisms that maintain HSV-1 in a latent state in sensory neurons may provide new approaches to reducing susceptibility to recurrent herpetic disease. After primary HSV-1 corneal infection, CD8+ T cells infiltrate the trigeminal ganglia (TGs) of mice, and are retained in latently infected ganglia. Here we demonstrate that CD8+ T cells that are present in the TGs at the time of excision can maintain HSV-1 in a latent state in sensory neurons in ex vivo TG cultures. Latently infected neurons expressed viral genome and some expressed HSV-1 immediate early and early proteins, but did not produce HSV-1 late proteins or infectious virions. Addition of anti-CD8α monoclonal antibody 5 d after culture initiation induced HSV-1 reactivation, as demonstrated by production of viral late proteins and infectious virions. Thus, CD8+ T cells can prevent HSV-1 reactivation without destroying the infected neurons. We propose that when the intrinsic capacity of neurons to inhibit HSV-1 reactivation from latency is compromised, production of HSV-1 immediate early and early proteins might activate CD8+ T cells aborting virion production.

scholarly journals Immunohistochemical Analysis of Primary Sensory Neurons Latently Infected with Herpes Simplex Virus Type 1

2000 ◽  
Vol 74 (1) ◽  
pp. 209-217 ◽  
Author(s):  
L. Yang ◽  
C. C. Voytek ◽  
T. P. Margolis
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Sensory Neurons ◽  
Latent Infection ◽  
Productive Infection ◽  
Viral Gene ◽  
Primary Sensory Neurons ◽  
Neuronal Populations ◽  
Latently Infected ◽  
Simplex Virus

ABSTRACT We characterized the populations of primary sensory neurons that become latently infected with herpes simplex virus (HSV) following peripheral inoculation. Twenty-one days after ocular inoculation with HSV strain KOS, 81% of latency-associated transcript (LAT)-positive trigeminal ganglion (TG) neurons coexpressed SSEA3, 71% coexpressed TrkA (the high-affinity nerve growth factor receptor), and 68% coexpressed antigen recognized by monoclonal antibody (MAb) A5; less than 5% coexpressed antigen recognized by MAb KH10. The distribution of LAT-positive, latently infected TG neurons contrasted sharply with (i) the overall distribution of neuronal phenotypes in latently infected TG and (ii) the neuronal distribution of viral antigen in productively infected TG. Similar results were obtained following ocular and footpad inoculation with KOS/62, a LAT deletion mutant in which the LAT promoter is used to drive expression of theEscherichia coli lacZ gene. Thus, although all neuronal populations within primary sensory ganglia appear to be capable of supporting a productive infection with HSV, some neuronal phenotypes are more permissive for establishment of a latent infection with LAT expression than others. Furthermore, expression of HSV LAT does not appear to play a role in this process. These findings indicate that there are marked differences in the outcome of HSV infection among the different neuronal populations in the TG and highlight the key role that the host neuron may play in regulating the repertoire of viral gene expression during the establishment of HSV latent infection.

scholarly journals Towards an Understanding of the Herpes Simplex Virus Type 1 Latency-Reactivation Cycle

2010 ◽  
Vol 2010 ◽  
pp. 1-18 ◽  
Author(s):  
Guey-Chuen Perng ◽  
Clinton Jones
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Productive Infection ◽  
Viral Gene ◽  
Trigeminal Ganglia ◽  
Simplex Virus ◽  
Hsv 1

Infection by herpes simplex virus type 1 (HSV-1) can cause clinical symptoms in the peripheral and central nervous system. Recurrent ocular shedding can lead to corneal scarring and vision loss making HSV-1 a leading cause of corneal blindness due to an infectious agent. The primary site of HSV-1 latency is sensory neurons within trigeminal ganglia. Periodically, reactivation from latency occurs resulting in virus transmission and recurrent disease. During latency, the latency-associated transcript (LAT) is abundantly expressed. LAT expression is important for the latency-reactivation cycle in animal models, in part, because it inhibits apoptosis, viral gene expression, and productive infection. A novel transcript within LAT coding sequences (AL3) and small nonprotein coding RNAs are also expressed in trigeminal ganglia of latently infected mice. In this review, an update of viral factors that are expressed during latency and their potential roles in regulating the latency-reactivation cycle is discussed.

scholarly journals Differential Expression of Immune Checkpoint Molecules on CD8+ T Cells Specific for Immunodominant and Subdominant Herpes Simplex Virus 1 Epitopes

2019 ◽  
Vol 94 (2) ◽  
Author(s):  
Kate L. Carroll ◽  
Lyndsay Avery ◽  
Benjamin R. Treat ◽  
Lawrence P. Kane ◽  
Paul R. Kinchington ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Gene Expression ◽  
Viral Reactivation ◽  
Viral Gene ◽  
Herpes Simplex Virus 1 ◽  
Latently Infected ◽  
Checkpoint Molecule ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Herpes simplex virus 1 (HSV-1) causes a lifelong infection of neurons that innervate barrier sites like the skin and mucosal surfaces like the eye. After primary infection of the cornea, the virus enters latency within the trigeminal ganglion (TG), from which it can reactivate throughout the life of the host. Viral latency is maintained, in part, by virus-specific CD8+ T cells that nonlethally interact with infected neurons. When CD8+ T cell responses are inhibited, HSV-1 can reactivate, and these recurrent reactivation events can lead to blinding scarring of the cornea. In the C57BL/6 mouse, CD8+ T cells specific for the immunodominant epitope from glycoprotein B maintain functionality throughout latency, while CD8+ T cells specific for subdominant epitopes undergo functional impairment that is associated with the expression of the inhibitory checkpoint molecule programmed death 1 (PD-1). Here, we investigate the checkpoint molecule T cell immunoglobulin and mucin domain-containing 3 (Tim-3), which has traditionally been associated with CD8+ T cell exhaustion. Unexpectedly, we found that Tim-3 was preferentially expressed on highly functional ganglionic CD8+ T cells during acute and latent HSV-1 infection. This, paired with data that show that Tim-3 expression on CD8+ T cells in the latently infected TG is influenced by viral gene expression, suggests that Tim-3 is an indicator of recent T cell stimulation, rather than functional compromise, in this model. We conclude that Tim-3 expression is not sufficient to define functional compromise during latency; however, it may be useful in identifying activated cells within the TG during HSV-1 infection. IMPORTANCE Without an effective means of eliminating HSV-1 from latently infected neurons, efforts to control the virus have centered on preventing viral reactivation from latency. Virus-specific CD8+ T cells within the infected TG have been shown to play a crucial role in inhibiting viral reactivation, and with a portion of these cells exhibiting functional impairment, checkpoint molecule immunotherapies have presented a potential solution to enhancing the antiviral response of these cells. In pursuing this potential treatment strategy, we found that Tim-3 (often associated with CD8+ T cell functional exhaustion) is not upregulated on impaired cells but instead is upregulated on highly functional cells that have recently received antigenic stimulation. These findings support a role for Tim-3 as a marker of activation rather than exhaustion in this model, and we provide additional evidence for the hypothesis that there is persistent viral gene expression in the HSV-1 latently infected TG.

scholarly journals HSV-1 Cytoplasmic Envelopment and Egress

2020 ◽  
Vol 21 (17) ◽  
pp. 5969 ◽  
Author(s):  
Imran Ahmad ◽  
Duncan W. Wilson
Keyword(s):  
Viral Gene Expression ◽  
Cell Junctions ◽  
Viral Gene ◽  
Genome Packaging ◽  
Human Neurons ◽  
Molecular Machinery ◽  
Infected Cells ◽  
Simplex Virus ◽  
Hsv 1

Herpes simplex virus type 1 (HSV-1) is a structurally complex enveloped dsDNA virus that has evolved to replicate in human neurons and epithelia. Viral gene expression, DNA replication, capsid assembly, and genome packaging take place in the infected cell nucleus, which mature nucleocapsids exit by envelopment at the inner nuclear membrane then de-envelopment into the cytoplasm. Once in the cytoplasm, capsids travel along microtubules to reach, dock, and envelope at cytoplasmic organelles. This generates mature infectious HSV-1 particles that must then be sorted to the termini of sensory neurons, or to epithelial cell junctions, for spread to uninfected cells. The focus of this review is upon our current understanding of the viral and cellular molecular machinery that enables HSV-1 to travel within infected cells during egress and to manipulate cellular organelles to construct its envelope.

scholarly journals Linker Histones Are Mobilized during Infection with Herpes Simplex Virus Type 1

2008 ◽  
Vol 82 (17) ◽  
pp. 8629-8646 ◽  
Author(s):  
Kristen L. Conn ◽  
Michael J. Hendzel ◽  
Luis M. Schang
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Genome Replication ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Histones interact with herpes simplex virus type 1 (HSV-1) genomes and localize to replication compartments early during infections. However, HSV-1 genomes do not interact with histones in virions and are deposited in nuclear domains devoid of histones. Moreover, late viral replication compartments are also devoid of histones. The processes whereby histones come to interact with HSV-1 genomes, to be later displaced, remain unknown. However, they would involve the early movement of histones to the domains containing HSV-1 genomes and the later movement away from them. Histones unbind from chromatin, diffuse through the nucleoplasm, and rebind at different sites. Such mobility is upregulated by, for example, phosphorylation or acetylation. We evaluated whether HSV-1 infection modulates histone mobility, using fluorescence recovery after photobleaching. All somatic H1 variants were mobilized to different degrees. H1.2, the most mobilized, was mobilized at 4 h and further so at 7 h after infection, resulting in increases in its “free” pools. H1.2 was mobilized to a “basal” degree under conditions of little to no HSV-1 protein expression. This basal mobilization required nuclear native HSV-1 genomes but was independent of HSV-1 proteins and most likely due to cellular responses. Mobilization above this basal degree, and increases in H1.2 free pools, however, depended on immediate-early or early HSV-1 proteins, but not on HSV-1 genome replication or late proteins. Linker histone mobilization is a novel consequence of cell-virus interactions, which is consistent with the dynamic interactions between histones and HSV-1 genomes during lytic infection; it may also participate in the regulation of viral gene expression.

scholarly journals Two Small RNAs Encoded within the First 1.5 Kilobases of the Herpes Simplex Virus Type 1 Latency-Associated Transcript Can Inhibit Productive Infection and Cooperate To Inhibit Apoptosis

2009 ◽  
Vol 83 (18) ◽  
pp. 9131-9139 ◽  
Author(s):  
Wenwen Shen ◽  
Mariana Sa e Silva ◽  
Tareq Jaber ◽  
Olga Vitvitskaia ◽  
Sumin Li ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Herpes Simplex Virus Type ◽  
Small Rnas ◽  
Productive Infection ◽  
Coding Sequences ◽  
Latently Infected ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) is abundantly expressed in latently infected trigeminal ganglionic sensory neurons. Expression of the first 1.5 kb of LAT coding sequences is sufficient for the wild-type reactivation phenotype in small animal models of infection. The ability of the first 1.5 kb of LAT coding sequences to inhibit apoptosis is important for the latency-reactivation cycle. Several studies have also concluded that LAT inhibits productive infection. To date, a functional LAT protein has not been identified, suggesting that LAT is a regulatory RNA. Two small RNAs (sRNAs) were previously identified within the first 1.5 kb of LAT coding sequences. In this study, we demonstrated that both LAT sRNAs were expressed in the trigeminal ganglia of mice latently infected with an HSV-1 strain that expresses LAT but not when mice were infected with a LAT null mutant. LAT sRNA1 and sRNA2 cooperated to inhibit cold shock-induced apoptosis in mouse neuroblastoma cells. LAT sRNA1, but not LAT sRNA2, inhibited apoptosis less efficiently than both sRNAs. When rabbit skin cells were cotransfected with plasmids that express LAT sRNA1 and HSV-1 genomic DNA, the amount of infectious virus released was reduced approximately 3 logs. Although LAT sRNA2 was less effective at inhibiting virus production, it inhibited expression of infected cell protein 4 (ICP4). Neither LAT sRNA had an obvious effect on ICP0 expression. These studies suggested that expression of two LAT sRNAs plays a role in the latency-reactivation cycle by inhibiting apoptosis and productive infection.

scholarly journals Herpes Simplex Virus Type 1 and Bovine Herpesvirus 1 Latency

2003 ◽  
Vol 16 (1) ◽  
pp. 79-95 ◽  
Author(s):  
Clinton Jones
Keyword(s):  
Herpes Simplex ◽  
Bovine Herpesvirus ◽  
Productive Infection ◽  
Trigeminal Ganglia ◽  
Bovine Herpesvirus 1 ◽  
Latently Infected ◽  
Herpesvirus 1 ◽  
Simplex Virus ◽  
Hsv 1

SUMMARY Primary infection by herpes simplex virus type 1 (HSV-1) can cause clinical symptoms in the peripheral and central nervous system, upper respiratory tract, and gastrointestinal tract. Recurrent ocular shedding leads to corneal scarring that can progress to vision loss. Consequently, HSV-1 is the leading cause of corneal blindness due to an infectious agent. Bovine herpesvirus 1 (BHV-1) has similar biological properties to HSV-1 and is a significant health concern to the cattle industry. Latency of BHV-1 and HSV-1 is established in sensory neurons of trigeminal ganglia, but latency can be interrupted periodically, leading to reactivation from latency and spread of infectious virus. The ability of HSV-1 and BHV-1 to reactivate from latency leads to virus transmission and can lead to recurrent disease in individuals latently infected with HSV-1. During latency, the only abundant HSV-1 RNA expressed is the latency-associated transcript (LAT). In latently infected cattle, the latency-related (LR) RNA is the only abundant transcript that is expressed. LAT and LR RNA are antisense to ICP0 or bICP0, viral genes that are crucial for productive infection, suggesting that LAT and LR RNA interfere with productive infection by inhibiting ICP0 or bICP0 expression. Numerous studies have concluded that LAT expression is important for the latency-reactivation cycle in animal models. The LR gene has recently been demonstrated to be required for the latency-reactivation cycle in cattle. Several recent studies have demonstrated that LAT and the LR gene inhibit apoptosis (programmed cell death) in trigeminal ganglia of infected animals and transiently transfected cells. The antiapoptotic properties of LAT map to the same sequences that are necessary for promoting reactivation from latency. This review summarizes our current knowledge of factors regulating the latency-reactivation cycle of HSV-1 and BHV-1.

scholarly journals General and Specific Alterations in Programming of Global Viral Gene Expression during Infection by VP16 Activation-Deficient Mutants of Herpes Simplex Virus Type 1

2002 ◽  
Vol 76 (24) ◽  
pp. 12758-12774 ◽  
Author(s):  
William C. Yang ◽  
G. V. Devi-Rao ◽  
Peter Ghazal ◽  
Edward K. Wagner ◽  
Steven J. Triezenberg
Keyword(s):  
Gene Expression ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Viral Gene Expression ◽  
Productive Infection ◽  
Viral Gene ◽  
Virion Protein ◽  
Activation Domain ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT During productive infection by herpes simplex virus 1 (HSV-1), viral gene expression occurs in a temporally regulated cascade in which transcription of the viral immediate-early (IE) genes is strongly stimulated by the virion protein VP16. We have employed an oligonucleotide microarray to examine the effect of VP16 mutations on the overall pattern of viral gene expression following infection of HeLa cells. This microarray detects essentially all HSV-1 transcripts with relative and absolute levels correlating well with known kinetics of expression. This analysis revealed that deletion of the VP16 activation domain sharply reduced overall viral gene expression; moreover, the pattern of this reduced expression varied greatly from the pattern of a wild-type (wt) infection. However, when this mutant virus was delivered at a high multiplicity of infection or in the presence of the cellular stress inducer hexamethylene bisacetamide, expression was largely restored to the wt levels and pattern. Infection with virions that deliver wt VP16 protein at the start of infection but synthesize only truncated VP16 resulted in a normal kinetic cascade. This suggests that newly synthesized VP16 does not play a significant role in the expression of later classes of transcripts. The VP16 activation domain comprises two subregions. Deletion of the C-terminal subregion resulted in minimal changes in the level and profile of gene expression compared to a normal (wt) cascade. In contrast, deletion of the N-terminal subregion reduced the overall expression levels and skewed the relative levels of IE transcripts but did not significantly alter the kinetic pattern of early and late transcript expression. We conclude that the general activation of IE gene transcription by VP16, but not the specific ratios of IE transcripts, is necessary for the subsequent ordered expression of viral genes. Moreover, this report establishes the feasibility of microarray analysis for globally assessing viral gene expression programs as a function of the conditions of infection.

scholarly journals Herpes Simplex Virus Type 1 Immediate-Early Protein ICP27 Is Required for Efficient Incorporation of ICP0 and ICP4 into Virions

2007 ◽  
Vol 82 (1) ◽  
pp. 268-277 ◽  
Author(s):  
Lenka Sedlackova ◽  
Stephen A. Rice
Keyword(s):  
Gene Expression ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Cytoplasmic Localization ◽  
Viral Particles ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Early in infection, herpes simplex virus type 1 (HSV-1) immediate-early (IE) proteins ICP0 and ICP4 localize to the nucleus, where they stimulate viral transcription. Later in infection, ICP0 and to a lesser extent ICP4 accumulate in the cytoplasm, but their biological role there is unknown. Previously, it was shown that the cytoplasmic localization of ICP0/4 requires the multifunctional IE protein ICP27, which is itself an activator of viral gene expression. Here, we identify a viral ICP27 mutant, d3-4, which is unable to efficiently localize ICP0 and ICP4 to the cytoplasm but which otherwise resembles wild-type HSV-1 in its growth and viral gene expression phenotypes. These results genetically separate the function of ICP27 that affects ICP0/4 localization from its other functions, which affect viral growth and gene expression. As both ICP0 and ICP4 are known to be minor virion components, we used d3-4 to test the hypothesis that the cytoplasmic localization of these proteins is required for their incorporation into viral particles. Consistent with this conjecture, d3-4 virions were found to lack ICP0 in their tegument and to have greatly reduced levels of ICP4. Thus, the cytoplasmic localization of ICP0 and ICP4 appears to be a prerequisite for the assembly of these important transcriptional regulatory proteins into viral particles. Furthermore, our results show that ICP27 plays a previously unrecognized role in determining the composition of HSV-1 virions.

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