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Open Access Publications from the University of California

Scholarly Works (2 results)

  • Article
  • Peer Reviewed
ICTS Publications (2017)

Herpes simplex virus 1 (HSV-1) establishes latency within the sensory neurons of the trigeminal ganglia (TG). HSV-specific memory CD8+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+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+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+CD8+T cells was detected in TG and corneas of protected C57BL/6 (B6) mice, but not in TG and corneas of nonprotected CXCL10-/-or CXCR3-/-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-/-mice, using the neurotropic adeno-associated virus type 8 (AAV8) vector, boosted the number and function of effector memory CD8+T cells (TEM) and tissue-resident memory CD8+T cells (TRM), but not of central memory CD8+T cells (TCM), locally within TG, and improved protection against recurrent herpesvirus infection and disease in CXCL10-/-deficient mice. These findings demonstrate that the CXCL10/CXCR3 chemokine pathway is critical in shaping CD8+T cell immunity, locally within latently infected tissues, which protects against recurrent herpesvirus infection and disease.IMPORTANCEWe determined how the CXCL10/CXCR3 pathway affects CD8+T cell responses to recurrent ocular herpesvirus infection and disease. Using a well-established 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+TEMand CD8+TRMcells 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 CXCL10 in trigeminal ganglia of latently infected CXCL10-deficient mice significantly restored the number of local antiviral CD8+TEMand CD8+TRMcells associated with protection against recurrent ocular herpes. Based on these findings, a novel "prime/pull" therapeutic ocular herpes vaccine strategy is proposed and discussed.

    Cover page: CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8<sup>+</sup>T<sub>EM</sub>and CD8<sup>+</sup>T<sub>RM</sub>Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease.Creative Commons 'BY' version 4.0 license
    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2017)
    HSV type 1 (HSV-1) is a prevalent human pathogen that infects >3.72 billion individuals worldwide and can cause potentially blinding recurrent corneal herpetic disease. HSV-1 establishes latency within sensory neurons of trigeminal ganglia (TG), and TG-resident CD8+ T cells play a critical role in preventing its reactivation. The repertoire, phenotype, and function of protective CD8+ T cells are unknown. Bolstering the apparent feeble numbers of CD8+ T cells in TG remains a challenge for immunotherapeutic strategies. In this study, a comprehensive panel of 467 HLA-A*0201-restricted CD8+ T cell epitopes was predicted from the entire HSV-1 genome. CD8+ T cell responses to these genome-wide epitopes were compared in HSV-1-seropositive symptomatic individuals (with a history of numerous episodes of recurrent herpetic disease) and asymptomatic (ASYMP) individuals (who are infected but never experienced any recurrent herpetic disease). Frequent polyfunctional HSV-specific IFN-γ+CD107a/b+CD44highCD62LlowCD8+ effector memory T cells were detected in ASYMP individuals and were primarily directed against three "ASYMP" epitopes. In contrast, symptomatic individuals have more monofunctional CD44highCD62LhighCD8+ central memory T cells. Furthermore, therapeutic immunization with an innovative prime/pull vaccine, based on priming with multiple ASYMP epitopes (prime) and neurotropic TG delivery of the T cell-attracting chemokine CXCL10 (pull), boosted the number and function of CD44highCD62LlowCD8+ effector memory T cells and CD103highCD8+ tissue-resident T cells in TG of latently infected HLA-A*0201-transgenic mice and reduced recurrent ocular herpes following UV-B-induced reactivation. These findings have profound implications in the development of T cell-based immunotherapeutic strategies to treat blinding recurrent herpes infection and disease.
      Cover page: Bolstering the Number and Function of HSV-1–Specific CD8+ Effector Memory T Cells and Tissue-Resident Memory T Cells in Latently Infected Trigeminal Ganglia Reduces Recurrent Ocular Herpes Infection and Disease
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