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

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.

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

Journal of Virology ◽

10.1128/jvi.01699-08 ◽

2008 ◽

Vol 83 (5) ◽

pp. 2237-2245 ◽

Cited By ~ 38

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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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

Journal of Virology ◽

10.1128/jvi.02234-08 ◽

2008 ◽

Vol 83 (5) ◽

pp. 2246-2254 ◽

Cited By ~ 55

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.

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Delaying the Expression of Herpes Simplex Virus Type 1 Glycoprotein B (gB) to a True Late Gene Alters Neurovirulence and Inhibits the gB-CD8+ T-Cell Response in the Trigeminal Ganglion

Journal of Virology ◽

10.1128/jvi.00496-10 ◽

2010 ◽

Vol 84 (17) ◽

pp. 8811-8820 ◽

Cited By ~ 16

Author(s):

Srividya Ramachandran ◽

Katherine A. Davoli ◽

Michael B. Yee ◽

Robert L. Hendricks ◽

Paul R. Kinchington

Keyword(s):

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Dna Synthesis ◽

Viral Dna ◽

Cd8 Cells ◽

Latently Infected ◽

Simplex Virus ◽

Hsv 1

ABSTRACT Following herpes simplex virus type 1 (HSV-1) ocular infection of C57BL/6 mice, activated CD8+ T cells specific for an immunodominant epitope on HSV-1 glycoprotein B (gB-CD8 cells) establish a stable memory population in HSV-1 latently infected trigeminal ganglia (TG), whereas non-HSV-specific CD8+ T cells are lost over time. The retention and activation of gB-CD8 cells appear to be influenced by persistent viral antigenic exposure within the latently infected TG. We hypothesized that the low-level expression of gB from its native promoter before viral DNA synthesis is critical for the retention and activation of gB-CD8 cells in the TG during HSV-1 latency and for their ability to block HSV-1 reactivation from latency. To test this, we created a recombinant HSV-1 in which gB is expressed only after viral DNA synthesis from the true late gC promoter (gCp-gB). Despite minor growth differences compared to its rescuant in infected corneas, gCp-gB was significantly growth impaired in the TG and produced a reduced latent genome load. The gCp-gB- and rescuant-infected mice mounted similar gB-CD8 effector responses, but the size and activation phenotypes of the memory gB-CD8 cells were diminished in gCp-gB latently infected TG, suggesting that the stimulation of gB-CD8 cells requires gB expression before viral DNA synthesis. Surprisingly, late gB expression did not compromise the capacity of gB-CD8 cells to inhibit HSV-1 reactivation from latency in ex vivo TG cultures, suggesting that gB-CD8 cells can block HSV-1 reactivation at a very late stage in the viral life cycle. These data have implications for designing better immunogens for vaccines to prevent HSV-1 reactivation.

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PD-L1/B7-H1 Regulates the Survival but Not the Function of CD8+T Cells in Herpes Simplex Virus Type 1 Latently Infected Trigeminal Ganglia

The Journal of Immunology ◽

10.4049/jimmunol.1300582 ◽

2013 ◽

Vol 190 (12) ◽

pp. 6277-6286 ◽

Cited By ~ 20

Author(s):

Sohyun Jeon ◽

Anthony J. St. Leger ◽

Thomas L. Cherpes ◽

Brian S. Sheridan ◽

Robert L. Hendricks

Keyword(s):

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Cd8 T Cells ◽

Herpes Simplex Virus Type ◽

Trigeminal Ganglia ◽

Latently Infected ◽

Simplex Virus

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Gamma Interferon Can Block Herpes Simplex Virus Type 1 Reactivation from Latency, Even in the Presence of Late Gene Expression

Journal of Virology ◽

10.1128/jvi.79.16.10339-10347.2005 ◽

2005 ◽

Vol 79 (16) ◽

pp. 10339-10347 ◽

Cited By ~ 87

Author(s):

Vilma Decman ◽

Paul R. Kinchington ◽

Stephen A. K. Harvey ◽

Robert L. Hendricks

Keyword(s):

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Herpes Simplex Virus Type ◽

Promoter Activity ◽

Latently Infected ◽

Ifn Γ ◽

Simplex Virus ◽

Hsv 1

ABSTRACT Herpes simplex virus type 1 (HSV-1)-specific CD8+ T cells and the cytokine gamma interferon (IFN-γ) are persistently present in trigeminal ganglia (TG) harboring latent HSV-1. We define “latency” as the retention of functional viral genomes in sensory neurons without the production of infectious virions and “reactivation” as a multistep process leading from latency to virion assembly. CD8+ T cells can block HSV-1 reactivation in ex vivo mouse TG cultures and appear to be the sole source of IFN-γ in these cultures. Here we demonstrate that IFN-γ alone can block HSV-1 reactivation in some latently infected neurons, and we identify points of intervention in the life cycle of the reactivating virus. Cell suspensions of TG that were latently infected with recombinant RE HSV-1 expressing enhanced green fluorescent protein from the promoter for infected cell protein 0 (ICP0) or glycoprotein C (gC) were depleted of endogenous CD8+ or CD45+ cells and cultured in the presence or absence of IFN-γ. Our results demonstrate that IFN-γ acts on latently infected neurons to inhibit (i) HSV-1 reactivation, (ii) ICP0 promoter activity, (iii) gC promoter activity, and (iv) reactivation in neurons in which the ICP0 or gC promoter is active. Interestingly, we detected transcripts for ICP0, ICP4, and gH in neurons that expressed the ICP0 promoter but were prevented by IFN-γ from reactivation and virion formation. Thus, the IFN-γ blockade of HSV-1 reactivation from latency in neurons is associated with an inhibition of the expression of the ICP0 gene (required for reactivation) and a blockade of a step that occurs after the expression of at least some viral structural genes.

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Entry of Herpes Simplex Virus Type 1 into Primary Sensory Neurons In Vitro Is Mediated by Nectin-1/HveC

Journal of Virology ◽

10.1128/jvi.77.5.3307-3311.2003 ◽

2003 ◽

Vol 77 (5) ◽

pp. 3307-3311 ◽

Cited By ~ 53

Author(s):

Sarah M. Richart ◽

Scott A. Simpson ◽

Claude Krummenacher ◽

J. Charles Whitbeck ◽

Lewis I. Pizer ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Sensory Neurons ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Primary Cultures ◽

Simplex Virus ◽

Hsv 1

ABSTRACT Primary cultures of rat and mouse sensory neurons were used to study the entry of herpes simplex virus type 1 (HSV-1). Soluble, truncated nectin-1 but not HveA prevented viral entry. Antibodies against nectin-1 also blocked infection of rat neurons. These results indicate that nectin-1 is the primary receptor for HSV-1 infection of sensory neurons.

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Effect of a combination therapy between IL-12 and soluble IL-4 receptor (sIL-4R) onCandida albicansand herpes simplex virus type 1 infections in thermally injured mice

Canadian Journal of Microbiology ◽

10.1139/w02-085 ◽

2002 ◽

Vol 48 (10) ◽

pp. 886-894 ◽

Cited By ~ 3

Author(s):

Makiko Kobayashi ◽

Hitoshi Takahashi ◽

David N Herndon ◽

Richard B Pollard ◽

Fujio Suzuki

Keyword(s):

T Cells ◽

Candida Albicans ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Herpes Simplex Virus Type ◽

Cell Responses ◽

Ifn Γ ◽

Simplex Virus ◽

Hsv 1

The effectiveness of a combination using IL-12 and soluble IL-4 receptor (sIL-4R) to treat severe infections of herpes simplex virus type 1 (HSV-1) and Candida albicans in thermally injured mice was investigated. Although sIL-4R decreased burn-associated type 2 T-cell responses, the effect of sIL-4R was minimal on the morbidity and mortality of thermally injured mice exposed to 250 times LD50of HSV-1 or 10 times LD50of C. albicans. Compared with 100% mortality in control mice, mortality for HSV-1 and C. albicans was 40 and 20%, respectively, in thermally injured mice that received IL-12 and sIL-4R in combination. After stimulation with anti-CD3 monoclonal antibody, splenic T cells from thermally injured mice exposed to large amounts of HSV-1 or C. albicans did not produce gamma interferon (IFN-γ) into their culture fluids. However, IFN-γ was produced by splenic T cells from thermally injured and infected mice treated with IL-12 and sIL-4R in combination. These results suggest that therapeutic treatment with a combination of IL-12 and sIL-4R may be effective by inducing type 1 T-cell responses in thermally injured mice exposed to large amounts of HSV-1 or C. albicans.Key words: burn, IL-12, soluble IL-4 receptor, herpesvirus, Candida albicans.

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

Journal of Virology ◽

10.1128/jvi.03481-14 ◽

2015 ◽

Vol 89 (10) ◽

pp. 5747-5750 ◽

Cited By ~ 2

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.

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