In the US, herpes simplex virus type 1 (HSV-1) is the most common cause of corneal blindness due to an infectious agent and the most common cause of sporadic lethal encephalitis in immune competent individuals. Most HSV-1 disease is due to viral reactivations rather than the primary acute infection. Thus understanding HSV-1 latency-reactivation is important for developing methods to combat HSV-1 diseases. HSV-1 uses herpes virus entry mediator, or HVEM, as one route of infecting cells. HVEM is a member of the TNF receptor superfamily and can regulate immune responses by acting as a molecular switch between proinflammatory and inhibitory signaling. When HVEM on a neuron binds to BTLA on a T cell, a bidirectional pathway is activated. Activated HVEM activates NF-kB which promotes neuronal cell survival by decreasing apoptosis. Activated BTLA limits T cell activation. Thus, increasing HVEM should block apoptosis and decrease T cell function - the same activities attributed to the HSV-1 LAT gene and that are thought to be involved in how LAT enhances latency/reactivation (although the mechanism(s) by which LAT blocks apoptosis and decreases T cell response are not known). Our preliminary and recently published results indicate that: 1)HSV-1 latency and reactivation are both significantly reduced in HVEM-/- mice and 2)Two small non-coding LAT RNAs (sncRNAs) can upregulate HVEM on neurons. Based on these findings we hypothesize that one mechanism by which LAT enhances latency and reactivation is by upregulating HVEM which in turn promotes HSV-1 latency and reactivation by decreasing both apoptosis and the local T cell response.
Our Specific Aims are: 1. Construct an HSV-1 double knockout (KO) mutant (DsncRNA1&2) that is KO'd for both LAT sncRNAs (sncRNA1 & sncRNA2). We expect that this mutant will no longer increase HVEM expression and will have reduced latency/reactivation similar to LAT(-) mutants. This would strongly support the hypothesis that the two LAT sncRNAs normally upregulate HVEM which in turn decreases apoptosis and T cell responses resulting in increased latency/reactivation. 2. Construct and analyze an HSV-1 mutant (DLAT-HVEM) that expresses HVEM driven by the LAT promoter on a LAT(-) genomic background. We expect the HVEM expressed by this mutant to restore wt LAT(+)- like latency/reactivation to the LAT(-) virus. This would strongly support the hypothesis that increasing HVEM expression is an important mechanism by which LAT enhances latency/reactivation. We expect successful completion of this exploratory R21 application to lead to an RO1 grant involving the mechanism of LAT upregulation of HVEM and the development of therapeutic interventions to block this upregulation or block components of the bidirectional HVEM pathway.

Public Health Relevance

In the US, herpes simplex virus type 1 (HSV-1) reactivation from latency is the most common cause of corneal blindness due to an infectious agent and the most common cause of sporadic lethal encephalitis in immune competent individuals. The studies in this proposal investigate the HSV-1 LAT gene's upregulation of HVEM on the surface of latently infected neurons and the subsequent increased latency/reactivation. A better understand of the molecular and immune mechanisms controlling latently/reactivation is needed for development of new and improved clinical therapies against HSV-1 induced blinding rHSK and sporadic encephalitis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Virology - B Study Section (VIRB)
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Beisel, Christopher E
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University of California Irvine
Schools of Medicine
United States
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Srivastava, Ruchi; Coulon, Pierre-Grégoire; Roy, Soumyabrata et al. (2018) Phenotypic and Functional Signatures of Herpes Simplex Virus-Specific Effector Memory CD73+CD45RAhighCCR7lowCD8+ TEMRA and CD73+CD45RAlowCCR7lowCD8+ TEM Cells Are Associated with Asymptomatic Ocular Herpes. J Immunol 201:2315-2330
Esteves, Pedro J; Abrantes, Joana; Baldauf, Hanna-Mari et al. (2018) The wide utility of rabbits as models of human diseases. Exp Mol Med 50:66
Lopes, Patricia P; Todorov, George; Pham, Thanh T et al. (2018) Laser Adjuvant-Assisted Peptide Vaccine Promotes Skin Mobilization of Dendritic Cells and Enhances Protective CD8+ TEM and TRM Cell Responses against Herpesvirus Infection and Disease. J Virol 92:
Khan, Arif A; Srivastava, Ruchi; Vahed, Hawa et al. (2018) Human Asymptomatic Epitope Peptide/CXCL10-Based Prime/Pull Vaccine Induces Herpes Simplex Virus-Specific Gamma Interferon-Positive CD107+ CD8+ T Cells That Infiltrate the Corneas and Trigeminal Ganglia of Humanized HLA Transgenic Rabbits and Protect again J Virol 92:
Srivastava, Ruchi; Hernández-Ruiz, Marcela; Khan, Arif A et al. (2018) CXCL17 Chemokine-Dependent Mobilization of CXCR8+CD8+ Effector Memory and Tissue-Resident Memory T Cells in the Vaginal Mucosa Is Associated with Protection against Genital Herpes. J Immunol 200:2915-2926
Nesburn, Anthony B; BenMohamed, Lbachir (2017) A Tribute to Professor Steven L. Wechsler (1948-2016): The Man and the Scientist. Curr Eye Res 42:161-162
Khan, Arif A; Srivastava, Ruchi; Chentoufi, Aziz A et al. (2017) 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. J Immunol 199:186-203
Srivastava, Ruchi; Khan, Arif A; Garg, Sumit et al. (2017) Human Asymptomatic Epitopes Identified from the Herpes Simplex Virus Tegument Protein VP13/14 (UL47) Preferentially Recall Polyfunctional Effector Memory CD44high CD62Llow CD8+ TEM Cells and Protect Humanized HLA-A*02:01 Transgenic Mice against Ocular Her J Virol 91:
Srivastava, Ruchi; Khan, Arif A; Chilukuri, Sravya et al. (2017) CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8+ TEM and CD8+ TRM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease. J Virol 91:
Perng, Guey-Chuen; Osorio, Nelson; Jiang, Xianzhi et al. (2016) Large Amounts of Reactivated Virus in Tears Precedes Recurrent Herpes Stromal Keratitis in Stressed Rabbits Latently Infected with Herpes Simplex Virus. Curr Eye Res 41:284-91

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