In the United States, herpes simplex virus type 1 (HSV-1) is the most common cause of corneal blindness due to an infectious agent. Most ocular herpes disease is due to viral reactivations from latently infected neurons of the trigeminal ganglia (TG), rather than to primary acute infection. Prevention of reactivations requires a complex interplay between the virus, the neurons, and the immune system. While the host's CD8+ T cells play a critical role in controlling HSV-1 reactivation from latently infected neurons of TG, the virus has evolved immune evasion strategies as a counter-defense to protect itself from being attacked by the host's CD8+ T cells. Understanding the mechanisms of HSV-1 immune evasion during latency has been enhanced by our recent discovery of dysfunctional HSV-specific CD8+ T cells in latently infected TG. This is triggered by the HSV-1 Latency Associated Transcript (LAT), the only viral gene abundantly transcribed during latent infection. Building on strong published and preliminary data, this application focuses on: (1) Understanding the LAT- mediated mechanisms that lead to dysfunctional CD8+ T cells in latently infected TG;and (2) Using that knowledge to devise novel powerful T-cell based immunotherapeutic strategies to prevent reactivations, recurrent eye disease and blindness. We have recently found that: (i) Three T-cell co-inhibitory receptors, PD- 1, TIM-3, and BTLA are highly expressed on HSV-specific CD8+ T cells, but not on HSV-specific CD4+ T cells, in TG from mice latently infected with LAT(+) compared to LAT(-) virus. (ii) A significant proportion of HSV- specific CD8+ T cells in LAT(+) TG are partially dysfunctional. (iii) PD-L1 and HVEM expression are increased in LAT(+) TG compared to LAT(-) TG. These intriguing results, together with related reports by others in the field, lead us to hypothesize that: (1) In HSV-1 latently infected TG, LAT promotes dysfunction of CD8+ T-cells and impairs their immuno-surveillance function through one or several T-cell inhibitory pathways, thus promoting virus reactivation from latently infected neurons;and (2) Reversing the dysfunction of CD8+ T-cells will decrease HSV-1 reactivation, recurrent eye disease, and prevent loss of sight.
Our specific Aims are:
Aim 1 : Determine the kinetics of expression of T-cell co-inhibitory receptors, PD-1, TIM-3, and BTLA, on TG-resident CD8+ T cells of """"""""humanized"""""""" HLA Tg mice ocularly infected with HSV-1 LAT(+) vs. HSV-1 LAT(-) and confirm the role of these co-inhibitory pathways in the dysfunction of CD8+ T-cells seen in latently infected TG.
Aim 2 : Test the hypothesis that in vivo blocking of PD-1/PD-L1, TIM-3/GAL-9 and/or BTLA/HVEM T-cell inhibitory signaling pathways will restore CD8+ T cell protective function and enhance the efficacy of therapeutic immunization in """"""""humanized"""""""" HLA Tg mice. This translational research, that gathers a multidisciplinary team, addresses the current NEI Audacious Goals Initiative: """"""""Development of new treatments through small molecules approach to treat eye disease and to restore sight."""""""" Successful completion of this pre-clinical study in """"""""humanized"""""""" HLA Tg mice should lead to a novel and powerful immunotherapy to prevent blinding recurrent herpetic disease.

Public Health Relevance

The goals of this translational project are: (1) to understand the T-cell co-inhibitory dependent mechanisms used by HSV-1 to evade CD8+ T cell immunosurveillance;(2) to use this information to devise a novel and powerful T cell-based immunotherapy with the potential to produce a sustained clinical response to blinding recurrent herpetic disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY024618-01
Application #
8753737
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Mckie, George Ann
Project Start
2014-09-03
Project End
2017-08-31
Budget Start
2014-09-03
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$386,250
Indirect Cost
$136,250
Name
University of California Irvine
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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:
Srivastava, Ruchi; Dervillez, Xavier; Khan, Arif A et al. (2016) 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. J Virol 90:3913-3928

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