scholarly journals The Herpes Simplex Virus Latency-Associated Transcript Gene Is Associated with a Broader Repertoire of Virus-Specific Exhausted CD8+T Cells Retained within the Trigeminal Ganglia of Latently Infected HLA Transgenic Rabbits

2016 ◽  
Vol 90 (8) ◽  
pp. 3913-3928 ◽  
Author(s):  
Ruchi Srivastava ◽  
Xavier Dervillez ◽  
Arif A. Khan ◽  
Aziz A. Chentoufi ◽  
Sravya Chilukuri ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex ◽  
Immune Evasion ◽  
Trigeminal Ganglia ◽  
Null Mutant ◽  
Wild Type ◽  
Transgenic Rabbits ◽  
Latently Infected ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTPersistent pathogens, such as herpes simplex virus 1 (HSV-1), have evolved a variety of immune evasion strategies to avoid being detected and destroyed by the host's immune system. A dynamic cross talk appears to occur between the HSV-1 latency-associated transcript (LAT), the only viral gene that is abundantly transcribed during latency, and the CD8+T cells that reside in HSV-1 latently infected human and rabbit trigeminal ganglia (TG). The reactivation phenotype of TG that are latently infected with wild-type HSV-1 or with LAT-rescued mutant (i.e., LAT+TG) is significantly higher than TG latently infected with LAT-null mutant (i.e., LAT−TG). Whether LAT promotes virus reactivation by selectively shaping a unique repertoire of HSV-specific CD8+T cells in LAT+TG is unknown. In the present study, we assessed the frequency, function, and exhaustion status of TG-resident CD8+T cells specific to 40 epitopes derived from HSV-1 gB, gD, VP11/12, and VP13/14 proteins, in human leukocyte antigen (HLA-A*0201) transgenic rabbits infected ocularly with LAT+versus LAT–virus. Compared to CD8+T cells from LAT–TG, CD8+T cells from LAT+TG (i) recognized a broader selection of nonoverlapping HSV-1 epitopes, (ii) expressed higher levels of PD-1, TIM-3, and CTLA-4 markers of exhaustion, and (iii) produced less tumor necrosis factor alpha, gamma interferon, and granzyme B. These results suggest a novel immune evasion mechanism by which the HSV-1 LAT may contribute to the shaping of a broader repertoire of exhausted HSV-specific CD8+T cells in latently infected TG, thus allowing for increased viral reactivation.IMPORTANCEA significantly larger repertoire of dysfunctional (exhausted) HSV-specific CD8+T cells were found in the TG of HLA transgenic rabbits latently infected with wild-type HSV-1 or with LAT-rescued mutant (i.e., LAT+TG) than in a more restricted repertoire of functional HSV-specific CD8+T cells in the TG of HLA transgenic rabbits latently infected with LAT-null mutant (i.e., LAT–TG). These findings suggest that the HSV-1 LAT locus interferes with the host cellular immune response by shaping a broader repertoire of exhausted HSV-specific CD8+T cells within the latency/reactivation TG site.

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.

scholarly journals Dok-1 and Dok-2 Are Required To Maintain Herpes Simplex Virus 1-Specific CD8+ T Cells in a Murine Model of Ocular Infection

2017 ◽  
Vol 91 (15) ◽  
Author(s):  
Soumia Lahmidi ◽  
Mitra Yousefi ◽  
Slimane Dridi ◽  
Pascale Duplay ◽  
Angela Pearson
Keyword(s):  
T Cells ◽  
Herpes Simplex ◽  
Acute Infection ◽  
T Cell Response ◽  
Ocular Infection ◽  
Trigeminal Ganglia ◽  
Herpes Simplex Virus 1 ◽  
Latently Infected ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Dok-1 and Dok-2 negatively regulate responses downstream of several immune receptors in lymphoid and myeloid cells. Recent evidence showed that Dok proteins are essential in the formation of memory CD8+ T cells to an exogenous epitope expressed by vaccinia virus; however, the importance of Dok-1 and Dok-2 in the control of viral infection is unknown. Here, we investigated the role of Dok proteins in modulating the immune response against herpes simplex virus 1 (HSV-1) in a mouse model of ocular infection. During acute infection, viral titers in the eye were similar in wild-type (WT) and Dok-1 and Dok-2 double-knockout (DKO) mice, and the percentages of infiltrating leukocytes were similar in DKO and WT corneas and trigeminal ganglia (TG). DKO mice exhibited a diminished CD8+ T cell response to the immunodominant HSV-1 glycoprotein B (gB) epitope in the spleen and draining lymph nodes compared to WT mice during acute infection. Remarkably, gB-specific CD8+ T cells almost completely disappeared in the spleens of DKO mice during latency, and the reduction of CD8+ effector memory T (Tem) cells was more severe than that of CD8+ central memory T (Tcm) cells. The percentage of gB-specific CD8+ T cells in TG during latency was also dramatically reduced in DKO mice; however, they were phenotypically similar to those from WT mice. In ex vivo assays, reactivation was detected earlier in TG cultures from infected DKO versus WT mice. Thus, Dok-1 and Dok-2 promote survival of gB-specific CD8+ T cells in TG latently infected with HSV-1. IMPORTANCE HSV-1 establishes lifelong latency in sensory neurons of trigeminal ganglia (TG). In humans, HSV-1 is able to sporadically reactivate from latently infected neurons and establish a lytic infection at a site to which the neurons project. Most herpetic disease in humans is due to reactivation of HSV-1 from latency rather than to primary acute infection. CD8+ T cells are thought to play an important role in controlling recurrent infections. In this study, we examined the involvement of Dok-1 and Dok-2 signaling proteins in the control of HSV-1 infection. We provide evidence that Dok proteins are required to maintain a CD8+ T cell response against HSV-1 during latency—especially CD8+ Tem cells—and that they negatively affect HSV-1 reactivation from latency. Elucidating Dok-mediated mechanisms involved in the control of HSV-1 reactivation from latency might contribute to the development of therapeutic strategies to prevent recurrent HSV-1-induced pathology.

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 Latent Herpes Simplex Virus 1 Infection Does Not Induce Apoptosis in Human Trigeminal Ganglia

2015 ◽  
Vol 89 (10) ◽  
pp. 5747-5750 ◽  
Author(s):  
Susanne Himmelein ◽  
Anja Lindemann ◽  
Inga Sinicina ◽  
Michael Strupp ◽  
Thomas Brandt ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Caspase 3 ◽  
Trigeminal Ganglia ◽  
Herpes Simplex Virus 1 ◽  
Reverse Transcription Quantitative Pcr ◽  
Latently Infected ◽  
Simplex Virus ◽  
Hsv 1

Herpes simplex virus 1 (HSV-1) can establish lifelong latency in human trigeminal ganglia. Latently infected ganglia contain CD8+T cells, which secrete granzyme B and are thus capable of inducing neuronal apoptosis. Using immunohistochemistry and single-cell reverse transcription-quantitative PCR (RT-qPCR), higher frequency and transcript levels of caspase-3 were found in HSV-1-negative compared to HSV-1-positive ganglia and neurons, respectively. No terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay-positive neurons were detected. The infiltrating T cells do not induce apoptosis in latently infected neurons.

scholarly journals Level of Herpes Simplex Virus Type 1 Latency Correlates with Severity of Corneal Scarring and Exhaustion of CD8+ T Cells in Trigeminal Ganglia of Latently Infected Mice

2008 ◽  
Vol 83 (5) ◽  
pp. 2246-2254 ◽  
Author(s):  
Kevin R. Mott ◽  
Catherine J. Bresee ◽  
Sariah J. Allen ◽  
Lbachir BenMohamed ◽  
Steven L. Wechsler ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Infected Individual ◽  
Trigeminal Ganglia ◽  
Corneal Scarring ◽  
Latently Infected ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT A hallmark of infection with herpes simplex virus type 1 (HSV-1) is the establishment of latency in ganglia of the infected individual. During the life of the latently infected individual, the virus can occasionally reactivate, travel back to the eye, and cause recurrent disease. Indeed, a major cause of corneal scarring (CS) is the scarring induced by HSV-1 following reactivation from latency. In this study, we evaluated the relationship between the amount of CS and the level of the HSV-1 latency-associated transcript (LAT) in trigeminal ganglia (TG) of latently infected mice. Our results suggested that the amount of CS was not related to the amount of virus replication following primary ocular HSV-1 infection, since replication in the eyes was similar in mice that did not develop CS, mice that developed CS in just one eye, and mice that developed CS in both eyes. In contrast, mice with no CS had significantly less LAT, and thus presumably less latency, in their TG than mice that had CS in both eyes. Higher CS also correlated with higher levels of mRNAs for PD-1, CD4, CD8, F4/80, interleukin-4, gamma interferon, granzyme A, and granzyme B in both cornea and TG. These results suggest that (i) the immunopathology induced by HSV-1 infection does not correlate with primary virus replication in the eye; (ii) increased CS appears to correlate with increased latency in the TG, although the possible cause-and-effect relationship is not known; and (iii) increased latency in mouse TG correlates with higher levels of PD-1 mRNA, suggesting exhaustion of CD8+ T cells.

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 Optimized Viral Dose and Transient Immunosuppression Enable Herpes Simplex Virus ICP0-Null Mutants To Establish Wild-Type Levels of Latency In Vivo

2000 ◽  
Vol 74 (13) ◽  
pp. 5957-5967 ◽  
Author(s):  
William P. Halford ◽  
Priscilla A. Schaffer
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Inoculum Size ◽  
Wild Type ◽  
Latently Infected ◽  
Viral Dose ◽  
Simplex Virus ◽  
Null Mutants ◽  
Hsv 1

ABSTRACT The reduced efficiency with which herpes simplex virus type 1 (HSV-1) mutants establish latent infections in vivo has been a fundamental obstacle in efforts to determine the roles of individual viral genes in HSV-1 reactivation. For example, in the absence of the “nonessential” viral immediate-early protein, ICP0, HSV-1 is severely impaired in its ability to (i) replicate at the site of inoculation and (ii) establish latency in neurons of the peripheral nervous system. The mouse ocular model of HSV latency was used in the present study to determine if the conditions of infection can be manipulated such that replication-impaired, ICP0-null mutants establish wild-type levels of latency, as measured by viral genome loads in latently infected trigeminal ganglia (TG). To this end, the effects of inoculum size and transient immunosuppression on the levels of acute replication in mouse eyes and of viral DNA in latently infected TG were examined. Following inoculation of mice with 2 × 103, 2 × 104, 2 × 105, or 2 × 106 PFU/eye, wild-type virus replicated in mouse eyes and established latency in TG with similar efficiencies at all four doses. In contrast, increasing the inoculum size of the ICP0-null mutants n212 and 7134 from 2 × 105 to 2 × 106PFU/eye significantly decreased the levels of infectious virus detected in the tear films of mice from days 4 to 9 postinfection. In an attempt to establish the biological basis for this finding, the effect of viral dose on the induction of the host proinflammatory response was examined. Quantitative reverse transcription-PCR demonstrated that increasing the inoculum of 7134 from 2 × 104 to 2 × 106 PFU/eye significantly increased the expression of proinflammatory (interleukin 6), cell adhesion (intercellular adhesion molecule 1), and phagocyte-associated (CD11b) genes in mouse eyes 24 h postinfection. Furthermore, transient immunosuppression of mice with cyclophosphamide, but not cyclosporin A, significantly enhanced both the levels of acute n212 and 7134 replication in the eye and the levels of mutant viral genomes present in latently infected TG in a dose-dependent manner. Thus, the results of this study demonstrate that acute replication in the eye and the number of ICP0-null mutant genomes in latently infected TG can be increased to wild-type levels for both n212 and 7134 by (i) optimization of inoculum size and (ii) transient immunosuppression with cyclophosphamide.

scholarly journals Circulating herpes simplex type 1 (HSV-1)-specific CD8+ T cells do not access HSV-1 latently infected trigeminal ganglia

Herpesviridae ◽  
2011 ◽  
Vol 2 (1) ◽  
pp. 5 ◽  
Author(s):  
Susanne Himmelein ◽  
Anthony J St Leger ◽  
Jared E Knickelbein ◽  
Alexander Rowe ◽  
Michael L Freeman ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex ◽  
Cd8 T Cells ◽  
Herpes Simplex Type ◽  
Trigeminal Ganglia ◽  
Latently Infected ◽  
Hsv 1

scholarly journals Reevaluating the CD8 T-Cell Response to Herpes Simplex Virus Type 1: Involvement of CD8 T Cells Reactive to Subdominant Epitopes

2008 ◽  
Vol 83 (5) ◽  
pp. 2237-2245 ◽  
Author(s):  
Brian S. Sheridan ◽  
Thomas L. Cherpes ◽  
Julie Urban ◽  
Pawel Kalinski ◽  
Robert L. Hendricks
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cd8 T Cells ◽  
Ex Vivo ◽  
T Cell Response ◽  
Latently Infected ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT In C57BL/6 (B6) mice, most herpes simplex virus (HSV)-specific CD8 T cells recognize a strongly immunodominant epitope on glycoprotein B (gB498) and can inhibit HSV type 1 (HSV-1) reactivation from latency in trigeminal ganglia (TG). However, half of the CD8 T cells retained in latently infected TG of B6 mice are not gB498 specific and have been largely ignored. The following observations from our current study indicate that these gB498-nonspecific CD8 T cells are HSV specific and may contribute to the control of HSV-1 latency. First, following corneal infection, OVA257-specific OT-1 CD8 T cells do not infiltrate the infected TG unless mice are simultaneously immunized with OVA257 peptide, and then they are not retained. Second, 30% of CD8 T cells in acutely infected TG that produce gamma interferon in response to HSV-1 stimulation directly ex vivo are gB498 nonspecific, and these cells maintain an activation phenotype during viral latency. Finally, gB498-nonspecific CD8 T cells are expanded in ex vivo cultures of latently infected TG and inhibit HSV-1 reactivation from latency in the absence of gB498-specific CD8 T cells. We conclude that many of the CD8 T cells that infiltrate and are retained in infected TG are HSV specific and potentially contribute to maintenance of HSV-1 latency. Identification of the viral proteins recognized by these cells will contribute to a better understanding of the dynamics of HSV-1 latency.

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