A hallmark of infection with HSV-1 is 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) also know as herpes stromal keratitis (HSK) is the scarring induced by HSV-1 following reactivation from latency. The most efficient way to decrease latency and thus subsequent recurrent infections and loss of vision is to reduce latency in trigeminal ganglia of infected mice. We have shown that recurrent HSV-1 infection was reduced significantly by depletion of DCs in immunized mice. The increase of latency and recurrences was associated with CD11c+CD8?+ DCs. Our previous studies support the concept that shifting the DCs population from CD11c+CD8?+ to CD11c+CD8?- DCs will reduce establishment of latency and the subsequent recurrences in latently infected mice. Consequently, because of the problems associated with recurrent ocular infection, preventing and/or reducing establishment of latency should be a major goal of a prophylactic immunization strategy against ocular HSV-1. Thus, based on our published and Preliminary Studies, we will use DCs stimulatory factors to shift the DCs population in order to reduce T cell exhaustion and consequently, the establishment/maintenance of latency in the TGs of ocularly infected mice. We propose to:
Aim : Test the hypothesis that pushing DCs toward myeloid-related (CD11c+CD8?-) and away from lymphoid-related (CD11c+CD8?+) will reduce latency in infected mice by decreasing T cell exhaustion in trigeminal ganglia of infected mice. Our published studies have shown that CD11c+CD8?+ DCs are involved in the enhancement of latency in the TGs of ocularly infected mice. In addition, our preliminary studies suggest that CD11c+CD8?+ DCs are involved in exhaustion of T cells and this T cell exhaustion is involved in the increase of latency. We will test whether: (a) Co-administration of pegylated GM-CSF with gD will enhance myeloid-related DCs and further reduce latency in immunized mice compared with mice that treated with GM- CSF and gD by reducing T cell exhaustion;and (b) Similar to pegylated-GM-CSF, activation of the lymphotoxin ? receptor (LT?r) with an agonist Ab will drive the expansion of CD11c+CD8?- and reduce latency and decrease T cell exhaustion in TGs of latently infected mice. The results of these studies will determine the importance of further stimulating CD11c+CD8?- DCs through the use of an immune stimulator to improve the efficacy of DNA immunization against HSV-1 latency. The long-term effects of these vaccine strategies will also be characterized to determine whether long-lived CD8+ T cell responses are elicited.

Public Health Relevance

One of the hallmarks of HSV infection is the ability of the virus to establish latency in neurons of an infected host. We have shown that lymphoid DCs are playing a major role in establishment of latency in trigeminal ganglia of infected mice and inclusion lymphoid DCs increases HSV-1 latency. We now plan to further reduce latency in trigeminal ganglia of infected mice by pushing the lymphoid DCs to myeloid DCs using pegylated-GM-CSF and anti-LT?R agonist.

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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Challberg, Mark D
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Cedars-Sinai Medical Center
Los Angeles
United States
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Mott, Kevin R; Maazi, Hadi; Allen, Sariah J et al. (2015) Batf3 deficiency is not critical for the generation of CD8?? dendritic cells. Immunobiology 220:518-24
Mott, Kevin R; Allen, Sariah J; Zandian, Mandana et al. (2014) Coregulatory interactions among CD8? dendritic cells, the latency-associated transcript, and programmed death 1 contribute to higher levels of herpes simplex virus 1 latency. J Virol 88:6599-610
Dumitrascu, O M; Mott, K R; Ghiasi, H (2014) A comparative study of experimental mouse models of central nervous system demyelination. Gene Ther 21:599-608
Matundan, Harry; Mott, Kevin R; Ghiasi, Homayon (2014) Role of CD8+ T cells and lymphoid dendritic cells in protection from ocular herpes simplex virus 1 challenge in immunized mice. J Virol 88:8016-27
Mott, Kevin R; Allen, Sariah J; Zandian, Mandana et al. (2014) Inclusion of CD80 in HSV targets the recombinant virus to PD-L1 on DCs and allows productive infection and robust immune responses. PLoS One 9:e87617
Mott, Kevin R; Allen, Sariah J; Zandian, Mandana et al. (2014) CD8? dendritic cells drive establishment of HSV-1 latency. PLoS One 9:e93444
Allen, Sariah J; Rhode-Kurnow, Antje; Mott, Kevin R et al. (2014) Interactions between herpesvirus entry mediator (TNFRSF14) and latency-associated transcript during herpes simplex virus 1 latency. J Virol 88:1961-71
Mott, Kevin R; Zandian, Mandana; Allen, Sariah J et al. (2013) Role of interleukin-2 and herpes simplex virus 1 in central nervous system demyelination in mice. J Virol 87:12102-9