The Herpes Simplex Virus 1 Latency-Associated Transcript Promotes Functional Exhaustion of Virus-Specific CD8
            <sup>+</sup>
            T Cells in Latently Infected Trigeminal Ganglia: a Novel Immune Evasion Mechanism

Chentoufi, Aziz Alami; Kritzer, Elizabeth; Tran, Michael V.; Dasgupta, Gargi; Lim, Chang Hyun; Yu, David C.; Afifi, Rasha E.; Jiang, Xianzhi; Carpenter, Dale; Osório, Nelson; Hsiang, Chinhui; Nesburn, Anthony B.; Wechsler, Steven L.; BenMohamed, Lbachir

doi:10.1128/jvi.00587-11

Cited by 65 publications

(94 citation statements)

References 84 publications

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“…These results are consistent with our recent finding of a significantly higher level of exhaustion of HSV-1 human epitope-specific CD8 ϩ T cells from TG of HLA Tg rabbits with higher virus reactivation compared to TG of HLA Tg rabbits with less virus reactivation (1,7,74). Because HSV-1 might coopt PD-1, TIM-3, 2B4, VISTA and/or TIGIT immune checkpoints as a strategy to evade CD8 ϩ T cell immune surveillance (70,75), a T cell-based immunotherapy will likely have to be combined with immune checkpoint blockade in order to reverse the dysfunction of antiviral CD8 ϩ T EM and CD8 ϩ T RM cells. Antibodies targeting the PD-1/PD-L1 (programmed death ligand 1) immune checkpoint have recently shown remarkable clinical safety and efficacy in other systems (76)(77)(78).…”

Section: Discussionsupporting

confidence: 82%

“…The amount of viral Ag produced in the latently infected TG of mice following UV-B reactivation is quite low, less than 1 positive neuron/TG (66)(67)(68)(69). Thus, it is likely that the CXCL10/CXCR3 chemokine pathway inhibits exhaustion of CD8 ϩ T cells in TG through mechanisms other than Ag persistence, as we previously discussed (70). Elucidating the mechanisms by which the CXCL10/CXCR3 pathway might be preventing CD8 ϩ T cell exhaustion is beyond the scope of the present study.…”

Section: Discussionmentioning

confidence: 71%

“…Elucidating the mechanisms by which the CXCL10/CXCR3 pathway might be preventing CD8 ϩ T cell exhaustion remains to be determined. It is likely that the CXCL10/CXCR3 chemokine pathway prevents exhaustion of CD8 ϩ T cells through mechanisms other than Ag persistence (70).…”

Section: Discussionmentioning

confidence: 99%

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CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 ⁺ T _EM and CD8 ⁺ T _RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

Srivastava

Khan

Chilukuri

et al. 2017

J Virol

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Herpes simplex virus 1 (HSV-1) establishes latency within the sensory neurons of the trigeminal ganglia (TG). HSV-specific memory CD8 ϩ T cells play a critical role in preventing HSV-1 reactivation from TG and subsequent virus shedding in tears that trigger recurrent corneal herpetic disease. The CXC chemokine ligand 10 (CXCL10)/CXC chemokine receptor 3 (CXCR3) chemokine pathway promotes T cell immunity to many viral pathogens, but its importance in CD8 ϩ T cell immunity to recurrent herpes has been poorly elucidated. In this study, we determined how the CXCL10/CXCR3 pathway affects TG-and cornea-resident CD8 ϩ T cell responses to recurrent ocular herpesvirus infection and disease using a well-established murine model in which HSV-1 reactivation was induced from latently infected TG by UV-B light. Following UV-B-induced HSV-1 reactivation, a significant increase in both the number and function of HSV-specific CXCR3 ϩ CD8 ϩ T cells was detected in TG and corneas of protected C57BL/6 (B6) mice, but not in TG and corneas of nonprotected CXCL10 Ϫ/Ϫ or CXCR3 Ϫ/Ϫ deficient mice. This increase was associated with a significant reduction in both virus shedding and recurrent corneal herpetic disease. Furthermore, delivery of exogenous CXCL10 chemokine in TG of CXCL10 Ϫ/Ϫ mice, using the neurotropic adeno-associated virus type 8 (AAV8) vector, boosted the number and function of effector memory CD8 ϩ T cells (T EM ) and tissue-resident memory CD8 ϩ T cells (T RM ), but not of central memory CD8 ϩ T cells (T CM ), locally within TG, and improved protection against recurrent herpesvirus infection and disease in CXCL10 Ϫ/Ϫ deficient mice. These findings demonstrate that the CXCL10/CXCR3 chemokine pathway is critical in shaping CD8 ϩ T cell immunity, locally within latently infected tissues, which protects against recurrent herpesvirus infection and disease.IMPORTANCE We determined how the CXCL10/CXCR3 pathway affects CD8 ϩ T cell responses to recurrent ocular herpesvirus infection and disease. Using a wellestablished murine model, in which HSV-1 reactivation in latently infected trigeminal ganglia was induced by UV-B light, we demonstrated that lack of either CXCL10 chemokine or its CXCR3 receptor compromised the mobilization of functional CD8 ϩ T EM and CD8 ϩ T RM cells within latently infected trigeminal ganglia following virus reactivation. This lack of T cell mobilization was associated with an increase in recurrent ocular herpesvirus infection and disease. Inversely, augmenting the amount of

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 71%

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CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 ⁺ T _EM and CD8 ⁺ T _RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

Srivastava

Khan

Chilukuri

et al. 2017

J Virol

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“…We have previously shown that LAT functions as an immune evasion gene (49,65), as an antiapoptosis gene (11), and as an inhibitor of productive infection (45). All three of these LAT functions would seemingly contribute to enhancing HSV-1 latency and the HSV-1 reactivation phenotype.…”

Section: Discussionmentioning

confidence: 99%

Interactions between Herpesvirus Entry Mediator (TNFRSF14) and Latency-Associated Transcript during Herpes Simplex Virus 1 Latency

Allen

Rhode-Kurnow

Mott

et al. 2014

J Virol

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f Herpesvirus entry mediator (HVEM) is one of several cell surface proteins herpes simplex virus (HSV) uses for attachment/entry. HVEM regulates cellular immune responses and can also increase cell survival. Interestingly, latency-associated transcript (LAT), the only viral gene consistently expressed during neuronal latency, enhances latency and reactivation by promoting cell survival and by helping the virus evade the host immune response. However, the mechanisms of these LAT activities are not well understood. We show here for the first time that one mechanism by which LAT enhances latency and reactivation appears to be by upregulating HVEM expression. HSV-1 latency/reactivation was significantly reduced in Hvem ؊/؊ mice, indicating that HVEM plays a significant role in HSV-1 latency/reactivation. Furthermore, LAT upregulated HVEM expression during latency in vivo and also when expressed in vitro in the absence of other viral factors. This study suggests a mechanism whereby LAT upregulates HVEM expression potentially through binding of two LAT small noncoding RNAs to the HVEM promoter and that the increased HVEM then leads to downregulation of immune responses in the latent microenvironment and increased survival of latently infected cells. Thus, one of the mechanisms by which LAT enhances latency/reactivation appears to be through increasing expression of HVEM.

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“…Более того, есть предположения ученых, основанные на современных исследованиях, свидетельствующие о том, что герпесвирусная инфекция в дальнейшем получит ещё более широкое распространение. Европейское региональное бюро ВОЗ, к при меру, герпетическую инфекцию отнесло в группу болезни, определяющую будущее инфекционной патологии [3,4,7,10,11].…”

Section: резюмеunclassified

Laboratory Examination of the Differences of the Secretory Immune System of Patients With Acute and Chronic Herpes Virus Infection

Базарный¹,

Bazarnyu²,

Zhuravlev³

et al. 2013

Actual Problems in Dentistry

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Scientific evidence on the secretory immunity of the oral mucosa in herpetic infections and their impact on the clinical features of the disease are mixed. The purpose of our study isimmunological comparison of patients with acute and chronic herpes infection. Our clinical and laboratory examination was based on 33 patients with acute exacerbation of chronic recurrent herpetic stomatitis, 35 patients with head ganglionitis herpes viral etiology and 26 persons of the control group. The results indicate big violations of secretory immunity of patients with herpes infection (decreased IF-a in typical viral ganlionitis and elevated LF – for recurrent stomatitis).

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The Herpes Simplex Virus 1 Latency-Associated Transcript Promotes Functional Exhaustion of Virus-Specific CD8 ⁺ T Cells in Latently Infected Trigeminal Ganglia: a Novel Immune Evasion Mechanism

Cited by 65 publications

References 84 publications

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 ⁺ T _EM and CD8 ⁺ T _RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 ⁺ T _EM and CD8 ⁺ T _RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

Interactions between Herpesvirus Entry Mediator (TNFRSF14) and Latency-Associated Transcript during Herpes Simplex Virus 1 Latency

Laboratory Examination of the Differences of the Secretory Immune System of Patients With Acute and Chronic Herpes Virus Infection

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The Herpes Simplex Virus 1 Latency-Associated Transcript Promotes Functional Exhaustion of Virus-Specific CD8 + T Cells in Latently Infected Trigeminal Ganglia: a Novel Immune Evasion Mechanism

Cited by 65 publications

References 84 publications

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 + T EM and CD8 + T RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 + T EM and CD8 + T RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

Interactions between Herpesvirus Entry Mediator (TNFRSF14) and Latency-Associated Transcript during Herpes Simplex Virus 1 Latency

Laboratory Examination of the Differences of the Secretory Immune System of Patients With Acute and Chronic Herpes Virus Infection

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Product

Resources

About

The Herpes Simplex Virus 1 Latency-Associated Transcript Promotes Functional Exhaustion of Virus-Specific CD8 ⁺ T Cells in Latently Infected Trigeminal Ganglia: a Novel Immune Evasion Mechanism

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 ⁺ T _EM and CD8 ⁺ T _RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 ⁺ T _EM and CD8 ⁺ T _RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease