scholarly journals Complete Genome Sequence of Herpes Simplex Virus 1 Strain McKrae

2019 ◽  
Vol 8 (39) ◽  
Author(s):  
Xiaoli Jiao ◽  
Hongyan Sui ◽  
Christopher Lyons ◽  
Bao Tran ◽  
Brad T. Sherman ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Single Molecule ◽  
Complete Sequence ◽  
Wild Type ◽  
Genetic Determinants ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Highly Virulent ◽  
Hsv 1

Herpes simplex virus 1 (HSV-1) strain McKrae is highly virulent and relatively neuroinvasive in animal models compared with other wild-type HSV-1 strains. To identify the genetic determinants that lead to the unique phenotypes of the McKrae strain, we sequenced its genome with PacBio single-molecule real-time (SMRT) technology and resolved the complete sequence.

scholarly journals Complete Genome Sequence of Herpes Simplex Virus 1 Strain MacIntyre

2019 ◽  
Vol 8 (37) ◽  
Author(s):  
Xiaoli Jiao ◽  
Hongyan Sui ◽  
Christopher Lyons ◽  
Bao Tran ◽  
Brad T. Sherman ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Single Molecule ◽  
Herpes Simplex Virus Type ◽  
Complete Sequence ◽  
Genetic Determinants ◽  
Sequencing Technology ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus

Herpes simplex virus type 1 (HSV-1) strain MacIntyre has a severe defect in the anterograde spread after replication in the nucleus. To better understand and identify the genetic determinants that lead to the unique phenotypes of the MacIntyre strain, we sequenced its genome with PacBio single-molecule real-time sequencing technology and resolved the complete sequence.

scholarly journals Herpes Simplex Virus 1 UL34 Protein Regulates the Global Architecture of the Endoplasmic Reticulum in Infected Cells

2017 ◽  
Vol 91 (12) ◽  
Author(s):  
Fumio Maeda ◽  
Jun Arii ◽  
Yoshitaka Hirohata ◽  
Yuhei Maruzuru ◽  
Naoto Koyanagi ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Null Mutation ◽  
Wild Type ◽  
Herpes Simplex Virus 1 ◽  
Nuclear Egress ◽  
Infected Cells ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Upon herpes simplex virus 1 (HSV-1) infection, the CD98 heavy chain (CD98hc) is redistributed around the nuclear membrane (NM), where it promotes viral de-envelopment during the nuclear egress of nucleocapsids. In this study, we attempted to identify the factor(s) involved in CD98hc accumulation and demonstrated the following: (i) the null mutation of HSV-1 UL34 caused specific dispersion throughout the cytoplasm of CD98hc and the HSV-1 de-envelopment regulators, glycoproteins B and H (gB and gH); (ii) as observed with CD98hc, gB, and gH, wild-type HSV-1 infection caused redistribution of the endoplasmic reticulum (ER) markers calnexin and ERp57 around the NM, whereas the UL34-null mutation caused cytoplasmic dispersion of these markers; (iii) the ER markers colocalized efficiently with CD98hc, gB, and gH in the presence and absence of UL34 in HSV-1-infected cells; (iv) at the ultrastructural level, wild-type HSV-1 infection caused ER compression around the NM, whereas the UL34-null mutation caused cytoplasmic dispersion of the ER; and (v) the UL34-null mutation significantly decreased the colocalization efficiency of lamin protein markers of the NM with CD98hc and gB. Collectively, these results indicate that HSV-1 infection causes redistribution of the ER around the NM, with resulting accumulation of ER-associated CD98hc, gB, and gH around the NM and that UL34 is required for ER redistribution, as well as for efficient recruitment to the NM of the ER-associated de-envelopment factors. Our study suggests that HSV-1 induces remodeling of the global ER architecture for recruitment of regulators mediating viral nuclear egress to the NM. IMPORTANCE The ER is an important cellular organelle that exists as a complex network extending throughout the cytoplasm. Although viruses often remodel the ER to facilitate viral replication, information on the effects of herpesvirus infections on ER morphological integrity is limited. Here, we showed that HSV-1 infection led to compression of the global ER architecture around the NM, resulting in accumulation of ER-associated regulators associated with nuclear egress of HSV-1 nucleocapsids. We also identified HSV-1 UL34 as a viral factor that mediated ER remodeling. Furthermore, we demonstrated that UL34 was required for efficient targeting of these regulators to the NM. To our knowledge, this is the first report showing that a herpesvirus remodels ER global architecture. Our study also provides insight into the mechanism by which the regulators for HSV-1 nuclear egress are recruited to the NM, where this viral event occurs.

scholarly journals Herpes Simplex Virus 1 Latency and the Kinetics of Reactivation Are Regulated by a Complex Network of Interactions between the Herpesvirus Entry Mediator, Its Ligands (gD, BTLA, LIGHT, and CD160), and the Latency-Associated Transcript

2018 ◽  
Vol 92 (24) ◽  
Author(s):  
Shaohui Wang ◽  
Alexander V. Ljubimov ◽  
Ling Jin ◽  
Klaus Pfeffer ◽  
Mitchell Kronenberg ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Trigeminal Ganglia ◽  
Wild Type ◽  
Herpes Simplex Virus 1 ◽  
Latently Infected ◽  
Simplex Virus ◽  
Kinetics Of ◽  
Herpesvirus Entry Mediator ◽  
Hsv 1

ABSTRACTRecently, we reported that the herpesvirus entry mediator (HVEM; also called TNFRSF14 or CD270) is upregulated by the latency-associated transcript (LAT) of herpes simplex virus 1 (HSV-1) and that the absence of HVEM affects latency reactivation but not primary infection in ocularly infected mice. gD has been shown to bind to HVEM. LIGHT (TNFSF14), CD160, and BTLA (B- and T-lymphocyte attenuator) also interact with HVEM and can interfere with HSV gD binding. It was not known if LIGHT, CD160, or BTLA affected the level of latency reactivation in the trigeminal ganglia (TG) of latently infected mice. To address this issue, we ocularly infected LIGHT−/−, CD160−/−, and BTLA−/−mice with LAT(+) and LAT(−) viruses, using similarly infected wild-type (WT) and HVEM−/−mice as controls. The amount of latency, as determined by the levels of gB DNA in the TG of the LIGHT−/−, CD160−/−, and BTLA−/−mice infected with either LAT(+) or LAT(−) viruses, was lower than that in WT mice infected with LAT(+) virus and was similar in WT mice infected with LAT(−) virus. The levels of LAT RNA in HVEM−/−, LIGHT−/−, CD160−/−, and BTLA−/−mice infected with LAT(+) virus were similar and were lower than the levels of LAT RNA in WT mice. However, LIGHT−/−, CD160−/−, and BTLA−/−mice, independent of the presence of LAT, had levels of reactivation similar to those of WT mice infected with LAT(+) virus. Faster reactivation correlated with the upregulation of HVEM transcript. The LIGHT−/−, CD160−/−, and BTLA−/−mice had higher levels of HVEM expression, and this, along with the absence of BTLA, LIGHT, or CD160, may contribute to faster reactivation, while the absence of each molecule, independent of LAT, may have contributed to lower latency. This study suggests that, in the absence of competition with gD for binding to HVEM, LAT RNA is important for WT levels of latency but not for WT levels of reactivation.IMPORTANCEThe effects of BTLA, LIGHT, and CD160 on latency reactivation are not known. We show here that in BTLA, LIGHT, or CD160 null mice, latency is reduced; however, HVEM expression is upregulated compared to that of WT mice, and this upregulation is associated with higher reactivation that is independent of LAT but dependent on gD expression. Thus, one of the mechanisms by which BTLA, LIGHT, and CD160 null mice enhance reactivation appears to be the increased expression of HVEM in the presence of gD. Thus, our results suggest that blockade of HVEM-LIGHT-BTLA-CD160 contributes to reduced HSV-1 latency and reactivation.

scholarly journals Herpes Simplex Virus 1 DNA Polymerase RNase H Activity Acts in a 3′-to-5′ Direction and Is Dependent on the 3′-to-5′ Exonuclease Active Site

2017 ◽  
Vol 92 (5) ◽  
Author(s):  
Jessica L. Lawler ◽  
Purba Mukherjee ◽  
Donald M. Coen
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Dna Polymerase ◽  
Polymerase Activity ◽  
Rnase H ◽  
Exonuclease Activity ◽  
Wild Type ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTThe catalytic subunit (Pol) of herpes simplex virus 1 (HSV-1) DNA polymerase has been extensively studied both as a model for other family B DNA polymerases and for its differences from these enzymes as an antiviral target. Among the activities of HSV-1 Pol is an intrinsic RNase H activity that cleaves RNA from RNA-DNA hybrids. There has long been a controversy regarding whether this activity is due to the 3′-to-5′ exonuclease of Pol or whether it is a separate activity, possibly acting on 5′ RNA termini. To investigate this issue, we compared wild-type HSV-1 Pol and a 3′-to-5′ exonuclease-deficient mutant, D368A Pol, for DNA polymerase activity, 3′-to-5′ exonuclease activity, and RNase H activityin vitro. Additionally, we assessed the RNase H activity using differentially end-labeled templates with 5′ or 3′ RNA termini. The mutant enzyme was at most modestly impaired for DNA polymerase activity but was drastically impaired for 3′-to-5′ exonuclease activity, with no activity detected even at high enzyme-to-DNA substrate ratios. Importantly, the mutant showed no detectable ability to excise RNA with either a 3′ or 5′ terminus, while the wild-type HSV-1 Pol was able to cleave RNA from the annealed RNA-DNA hairpin template, but only detectably with a 3′ RNA terminus in a 3′-to-5′ direction and at a rate lower than that of the exonuclease activity. These results suggest that HSV-1 Pol does not have an RNase H separable from its 3′-to-5′ exonuclease activity and that this activity prefers DNA degradation over degradation of RNA from RNA-DNA hybrids.IMPORTANCEHerpes simplex virus 1 (HSV-1) is a member of theHerpesviridaefamily of DNA viruses, several of which cause morbidity and mortality in humans. Although the HSV-1 DNA polymerase has been studied for decades and is a crucial target for antivirals against HSV-1 infection, several of its functions remain to be elucidated. A hypothesis suggesting the existence of a 5′-to-3′ RNase H activity intrinsic to this enzyme that could remove RNA primers from Okazaki fragments has been particularly controversial. In this study, we were unable to identify RNase H activity of HSV-1 DNA polymerase on RNA-DNA hybrids with 5′ RNA termini. We detected RNase H activity on hybrids with 3′ termini, but this was due to the 3′-to-5′ exonuclease. Thus, HSV-1 is unlikely to use this method to remove RNA primers during DNA replication but may use pathways similar to those used in eukaryotic Okazaki fragment maturation.

scholarly journals Phosphorylation of Herpes Simplex Virus 1 dUTPase Upregulated Viral dUTPase Activity To Compensate for Low Cellular dUTPase Activity for Efficient Viral Replication

2014 ◽  
Vol 88 (14) ◽  
pp. 7776-7785 ◽  
Author(s):  
Akihisa Kato ◽  
Yoshitaka Hirohata ◽  
Jun Arii ◽  
Yasushi Kawaguchi
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Viral Replication ◽  
Enzymatic Activity ◽  
Wild Type ◽  
Herpes Simplex Virus 1 ◽  
Wild Type Level ◽  
Simplex Virus ◽  
Efficient Viral Replication ◽  
Hsv 1

ABSTRACTWe recently reported that herpes simplex virus 1 (HSV-1) protein kinase Us3 phosphorylated viral dUTPase (vdUTPase) at serine 187 (Ser-187) to upregulate its enzymatic activity, which promoted HSV-1 replication in human neuroblastoma SK-N-SH cells but not in human carcinoma HEp-2 cells. In the present study, we showed that endogenous cellular dUTPase activity in SK-N-SH cells was significantly lower than that in HEp-2 cells and that overexpression of cellular dUTPase in SK-N-SH cells increased the replication of an HSV-1 mutant with an alanine substitution for Ser-187 (S187A) in vdUTPase to the wild-type level. In addition, we showed that knockdown of cellular dUTPase in HEp-2 cells significantly reduced replication of the mutant vdUTPase (S187A) virus but not that of wild-type HSV-1. Furthermore, the replacement of Ser-187 in vdUTPase with aspartic acid, which mimics constitutive phosphorylation, and overexpression of cellular dUTPase restored viral replication to the wild-type level in cellular dUTPase knockdown HEp-2 cells. These results indicated that sufficient dUTPase activity was required for efficient HSV-1 replication and supported the hypothesis that Us3 phosphorylation of vdUTPase Ser-187 upregulated vdUTPase activity in host cells with low cellular dUTPase activity to produce efficient viral replication.virus.IMPORTANCEIt has long been assumed that dUTPase activity is important for replication of viruses encoding a dUTPase and that the viral dUTPase (vdUTPase) activity was needed if host cell dUTPase activity was not sufficient for efficient viral replication. In the present study, we showed that the S187A mutation in HSV-1 vdUTPase, which impaired its enzymatic activity, reduced viral replication in SK-N-SH cells, which have low endogenous cellular dUTPase activity, and that overexpression of cellular dUTPase restored viral replication to the wild-type level. We also showed that knockdown of cellular dUTPase in HEp-2 cells, which have higher dUTPase activity than do SK-N-SH cells, reduced replication of HSV-1 with the vdUTPase mutation but had no effect on wild-type virus replication. This is the first report, to our knowledge, directly showing that dUTPase activity is critical for efficient viral replication and that vdUTPase compensates for low host cell dUTPase activity to produce efficient viral replication.

scholarly journals State and Role of Src Family Kinases in Replication of Herpes Simplex Virus 1

2006 ◽  
Vol 80 (7) ◽  
pp. 3349-3359 ◽  
Author(s):  
Yu Liang ◽  
Bernard Roizman
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Mutant Cell ◽  
Src Kinase ◽  
Src Family Kinases ◽  
Wild Type ◽  
Herpes Simplex Virus 1 ◽  
Kinase Family ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT An earlier report showed that infected cell protein no. 0 (ICP0) of herpes simplex virus 1 (HSV-1) interacts with the SH3 domains of a recently discovered adaptor protein, CIN85. Here, we report the following. (i) ICP0 also interacts with other SH3 domain-containing proteins and, in particular, with nonneuronal members of the Src kinase family. (ii) HSV-1 infection enhanced the activating phosphorylation of Tyr416 of the members of the Src kinase family, modestly enhanced the kinase activity of Src, and posttranslationally modified at least one additional member of the Src kinase family by phosphorylation in a manner dependent on the viral gene products ICP0, unique short 3 (US3), and unique long 13 (UL13). (iii) To define the roles of Src kinase family members, we examined the accumulation of viral proteins, DNA, and mRNA and virus yields from wild-type mouse embryo fibroblasts and sibling cells lacking Src, Fyn, and Yes (SYF−); a mutant cell line, +Src, in which Src was restored to SYF− cells; and the mutant cell line (CSK−) lacking the negative regulator Csk gene of the Src kinase family. Representative α, β, and γ2 proteins accumulated in the largest amounts in SYF− cells and the smallest amounts in +Src compared to wild-type cells. The CSK− cells yielded smaller amounts of the γ2 protein and at least 10-fold less virus than wild-type cells. We conclude that HSV-1 proteins regulate the activities of Src family kinases to achieve optimal viral yields in the course of viral replication.

scholarly journals HCFC1R1 Deficiency Blocks Herpes Simplex Virus-1 Infection by Inhibiting Nuclear Translocation of HCFC1 and VP16

2020 ◽  
Author(s):  
Yangkun Shen ◽  
Zhoujie Ye ◽  
Xiangqian Zhao ◽  
Zhihua Feng ◽  
Jinfeng Chen ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Host Cell ◽  
Host Cells ◽  
The Novel ◽  
Wild Type ◽  
Herpes Simplex Virus 1 ◽  
Novel Target ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTUpon HSV-1 infection, viral protein 16 (VP16), supported by Host Cell Factor C1 (HCFC1), is rapidly transported into the nucleus, and help to express a series of HSV-1 immediate-early proteins to begin its lytic replication. However, no direct evidence has shown if the HCFC1 deficiency can affect the proliferation of HSV-1 so far. Here, we showed that the HCFC1 deficiency led to a strong resistance to HSV-1 infection. Moreover, we identified Host Cell Factor C1 Regulator 1 (HCFC1R1) as a new host factor acting early in HSV infection for the transport of the HSV-1 capsid to the nucleus. The HCFC1R1 deficiency also led to a strong resistance to HSV-1 infection. The HCFC1R1 deficiency did not affect the attachment of HSV-1 to host cells but act early in HSV-1 infection by perturbing the formation of HCFC1/VP16 complex. Remarkably, in addition to wild-type HSV-1 infection, the host cells in the absence of either HCFC1 or HCFC1R1 showed strong resistant to the infection of TK-deficient HSV-1, which strain can course severe symptoms and tolerate to the current anti-HSV drug Acyclovir. Our data suggest that HCFC1 or HCFC1R1 may be used as the novel target for developing anti-HSV-1 therapies.IMPORTANCEHerpes simplex virus-1 (HSV-1) is widely spread in the human population and can cause a variety of herpetic diseases. Acyclovir, a guanosine analogue that targets the TK protein of HSV-1, is the first specific and selective anti-HSV-1 drug. However, the rapid emergence of resistant HSV-1 strains is occurring worldwide, endangering the efficacy of Acyclovir. Alternatively, targeting host factors is another strategy to stop HSV-1 infection. Unfortunately, although the HSV-1’s receptor, Nectin-1, was discovered in 1998, no effective antiviral drug to date has been developed by targeting Nectin-1. Targeting multiple pathways is the ultimate choice to prevent HSV-1 infection. Here we demonstrated that the deletion of HCFC1 or HCFC1R1 exhibits a strong inhibitory effect on both wild-type and TK-deficient HSV-1. Overall, we present evidence that HCFC1 or HCFC1R1 may be used as the novel target for developing anti-HSV-1 therapies with a defined mechanism of action.

scholarly journals Protein Kinase B/Akt Is Present in Activated Form throughout the Entire Replicative Cycle of ΔUS3 Mutant Virus but Only at Early Times after Infection with Wild-Type Herpes Simplex Virus 1

2006 ◽  
Vol 80 (7) ◽  
pp. 3341-3348 ◽  
Author(s):  
Luca Benetti ◽  
Bernard Roizman
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Protein Kinase ◽  
Protein Kinase B ◽  
Mutant Virus ◽  
Wild Type ◽  
Herpes Simplex Virus 1 ◽  
Infected Cells ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The product of the herpes simplex virus 1 (HSV-1) US3 gene is a multifunctional serine-threonine protein kinase that can block apoptosis induced by proapoptotic cellular proteins, exogenous agents, or replication-defective viruses. Earlier studies showed that the US3 kinase activates and functionally overlaps cellular protein kinase A (PKA). In this study we examined the status of phosphatidylinositol 3-kinase [PI(3)K] and of its effector, protein kinase B/Akt (PKB/Akt), a component of a major pathway of mammalian antiapoptotic signaling systems. We report the following. (i) Infection of target cells with HSV-1 induces transient phosphorylation of serine 473 of PKB/Akt early in infection, with a mechanism that is dependent on PI(3)K. Inhibition of PI(3)K induced apoptosis in mock-infected or ΔUS3 mutant-virus-infected but not in wild-type-virus-infected cells and reduced the accumulation of specific viral gene products, including the US3 protein kinase, but had a marginal effect on virus yields. (ii) At later times after infection, the total amounts of PKB/Akt decreased and phosphorylated PKB/Akt forms disappeared in a US3-dependent and protein phosphatase 2A-independent manner. (iii) Activation of PKA by forskolin did not mediate significant dephosphorylation of PKB/Akt. Our results are consistent with the model that PKB/Akt is activated early in infection and acts to block apoptosis in infected cells prior to the accumulation of US3 protein kinase and that it persists and continues to function as an antiapoptotic protein in the absence of US3 but becomes redundant or even inimical once US3 protein kinase accumulates in effective amounts.

scholarly journals Herpes Simplex Virus 1 Mutant with Point Mutations inUL39Is Impaired for Acute Viral Replication in Mice, Establishment of Latency, and Explant-Induced Reactivation

2018 ◽  
Vol 92 (7) ◽  
Author(s):  
Heba H. Mostafa ◽  
Thornton W. Thompson ◽  
Adam J. Konen ◽  
Steve D. Haenchen ◽  
Joshua G. Hilliard ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Ribonucleotide Reductase ◽  
Large Subunit ◽  
Wild Type ◽  
Herpes Simplex Virus 1 ◽  
Protein Levels ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTIn the process of generating herpes simplex virus 1 (HSV-1) mutations in the viral regulatory gene encoding infected cell protein 0 (ICP0), we isolated a viral mutant, termed KOS-NA, that was severely impaired for acute replication in the eyes and trigeminal ganglia (TG) of mice, defective in establishing a latent infection, and reactivated poorly from explanted TG. To identify the secondary mutation(s) responsible for the impaired phenotypes of this mutant, we sequenced the KOS-NA genome and noted that it contained two nonsynonymous mutations inUL39, which encodes the large subunit of ribonucleotide reductase, ICP6. These mutations resulted in lysine-to-proline (residue 393) and arginine-to-histidine (residue 950) substitutions in ICP6. To determine whether alteration of these amino acids was responsible for the KOS-NA phenotypesin vivo, we recombined the wild-type UL39 gene into the KOS-NA genome and rescued its acute replication phenotypes in mice. To further establish the role ofUL39in KOS-NA's decreased pathogenicity, theUL39mutations were recombined into HSV-1 (generating UL39mut), and this mutant virus showed reduced ocular and TG replication in mice comparable to that of KOS-NA. Interestingly, ICP6 protein levels were reduced in KOS-NA-infected cells relative to the wild-type protein. Moreover, we observed that KOS-NA does not counteract caspase 8-induced apoptosis, unlike wild-type strain KOS. Based on alignment studies with other HSV-1 ICP6 homologs, our data suggest that amino acid 950 of ICP6 likely plays an important role in ICP6 accumulation and inhibition of apoptosis, consequently impairing HSV-1 pathogenesis in a mouse model of HSV-1 infection.IMPORTANCEHSV-1 is a major human pathogen that infects ∼80% of the human population and can be life threatening to infected neonates or immunocompromised individuals. Effective therapies for treatment of recurrent HSV-1 infections are limited, which emphasizes a critical need to understand in greater detail the events that modulate HSV-1 replication and pathogenesis. In the current study, we identified a neuroattenuated HSV-1 mutant (i.e., KOS-NA) that contains novel mutations in the UL39 gene, which codes for the large subunit of ribonucleotide reductase (also known as ICP6). This mutant form of ICP6 was responsible for the attenuation of KOS-NAin vivoand resulted in diminished ICP6 protein levels and antiapoptotic effect. Thus, we have determined that subtle alteration of the UL39 gene regulates expression and functions of ICP6 and severely impacts HSV-1 pathogenesis, potentially making KOS-NA a promising vaccine candidate against HSV-1.

scholarly journals CD8+T Cells Play a Bystander Role in Mice Latently Infected with Herpes Simplex Virus 1

2016 ◽  
Vol 90 (10) ◽  
pp. 5059-5067 ◽  
Author(s):  
Kevin R. Mott ◽  
David Gate ◽  
Harry H. Matundan ◽  
Yasamin N. Ghiasi ◽  
Terrence Town ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Trigeminal Ganglia ◽  
Wild Type ◽  
Herpes Simplex Virus 1 ◽  
Link Type ◽  
Latently Infected ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTBased on an explant reactivation model, it has been proposed that CD8+T cells maintain latency in trigeminal ganglia (TG) of mice latently infected with herpes simplex virus 1 (HSV-1) [T. Liu, K. M. Khanna, X. Chen, D. J. Fink, and R. L. Hendricks, J Exp Med 191:1459–1466, 2000, doi:10.1084/jem.191.9.1459; K. M. Khanna, R. H. Bonneau, P. R. Kinchington, and R. L. Hendricks, Immunity 18:593-603, 2003, doi:10.1016/S1074-7613(03)00112-2]. In those studies, BALB/c mice were ocularly infected with an avirulent HSV-1 strain (RE) after corneal scarification. However, in our studies, we typically infect mice with a virulent HSV-1 strain (McKrae) that does not require corneal scarification. Using a combination of knockout mice, adoptive transfers, and depletion studies, we recently found that CD8α+dendritic cells (DCs) contribute to HSV-1 latency and reactivation in TG of ocularly infected mice (K. R. Mott, S. J. Allen, M. Zandian, B. Konda, B. G. Sharifi, C. Jones, S. L. Wechsler, T. Town, and H. Ghiasi, PLoS One 9:e93444, 2014, doi:10.1371/journal.pone.0093444). This suggested that CD8+T cells might not be the major regulators of HSV-1 latency in the mouse TG. To investigate this iconoclastic possibility, we used a blocking CD8 antibody and CD8+T cells in reactivated TG explants from mice latently infected with (i) the avirulent HSV-1 strain RE following corneal scarification or (ii) the virulent HSV-1 strain McKrae without corneal scarification. Independently of the strain or approach, our results show that CD8α+DCs, not CD8+T cells, drive latency and reactivation. In addition, adoptive transfer of CD8+T cells from wild-type (wt) mice to CD8α−/−mice did not restore latency to the level for wt mice or wt virus. In the presence of latency-associated transcript (LAT(+); wt virus), CD8+T cells seem to play a bystander role in the TG. These bystander T cells highly express PD-1, most likely due to the presence of CD8α+DCs. Collectively, these results support the notion that CD8+T cells do not play a major role in maintaining HSV-1 latency and reactivation.SIGNIFICANCEThis study addresses a fundamentally important and widely debated issue in the field of HSV latency—reactivation. In this article, we directly compare the effects of anti-CD8 antibody, CD8+T cells, LAT, and CD8α+DCs in blocking explant reactivation in TG of mice latently infected with avirulent or virulent HSV-1. Our data suggest that CD8+T cells are not responsible for an increase or maintenance of latency in ocularly infected mice. However, they seem to play a bystander role that correlates with the presence of LAT, higher subclinical reactivation levels, and higher PD-1 expression levels.

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