Recently, we made, I believe, a quite remarkable observation that could change how we deal with persistent viral infections. In a murine model of protracted infection that naturally occurs after exposure to the lymphocytic choriomeningitis virus (LCMV) variant Clone 13, we observed that a significant amount of IL-10 is produced, which interestingly coincides with the loss of the systemic cytotoxic T cell response against the virus. In our published studies, systemic administration of an antibody against the IL-10 receptor led to rapid resolution of the persistent infection, as demonstrated by weight gain and reduced viral load in the treated mice, in the absence of systemic side effects or immunopathology. This successful and innovative approach to treating a persistent viral infection constitutes a departure from classical vaccine strategies that have attempted to enhance the anti-viral response by directly inducing or amplifying anti-viral effector T cells. Indeed, such conventional approaches have failed to resolve LCMV Clone 13 infection in previous studies. We therefore suggest that therapeutic agents that block IL-10 receptor may hold great promise for the treatment of persistent viral infections in humans such as HCV and possibly HIV or CMV. In the proposed experiments, we would like to: 1. How chronic infection elicits systemic IL-10 production from DCs, CD4 and CD8 lymphocytes. Based on our findings, our working hypothesis is that CD8a negative DCs are the main drivers of IL-10 production from anti-viral responder cells. This subset is relatively enriched over CD8a positive DCs in chronically infected mice, because CD8 a pos DCs, which drive anti-viral IFN? production, are eliminated. We propose that early viral infection of this subset renders them more susceptible to CTL killing in vivo. 2. Translate the use of IL-10R blockade to the clinic by establishing paradigms for synergy in combination therapies with PD-1/PD-1L blockade, antiviral drugs and anti-viral vaccines A direct comparison of persistent versus acute infection with LCMV will form the basis for this investigation. The results should offer sufficient insight to enable the translation of this novel treatment to human persistent viral infections. In order to assure that our findings reach those groups working on HIV and HCV, cooperations have been established with leading groups in the field.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI068818-03S1
Application #
7919813
Study Section
Special Emphasis Panel (ZRG1-IMM-E (02))
Program Officer
Park, Eun-Chung
Project Start
2009-09-17
Project End
2011-08-31
Budget Start
2009-09-17
Budget End
2011-08-31
Support Year
3
Fiscal Year
2009
Total Cost
$207,044
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Baca Jones, Carmen; Filippi, Christophe; Sachithanantham, Sowbarnika et al. (2014) Direct infection of dendritic cells during chronic viral infection suppresses antiviral T cell proliferation and induces IL-10 expression in CD4 T cells. PLoS One 9:e90855
Boettler, Tobias; Choi, Youn Soo; Salek-Ardakani, Shahram et al. (2013) Exogenous OX40 stimulation during lymphocytic choriomeningitis virus infection impairs follicular Th cell differentiation and diverts CD4 T cells into the effector lineage by upregulating Blimp-1. J Immunol 191:5026-35
Boettler, Tobias; Moeckel, Friedrich; Cheng, Yang et al. (2012) OX40 facilitates control of a persistent virus infection. PLoS Pathog 8:e1002913
Boettler, Tobias; Cunha-Neto, Edecio; Kalil, Jorge et al. (2012) Can an immune-regulatory vaccine prevent HIV infection? Expert Rev Anti Infect Ther 10:299-305
Fousteri, Georgia; Dave, Amy; Juedes, Amy et al. (2011) Increased memory conversion of naive CD8 T cells activated during late phases of acute virus infection due to decreased cumulative antigen exposure. PLoS One 6:e14502
Fousteri, Georgia; Dave, Amy; Morin, Bret et al. (2011) Nasal cardiac myosin peptide treatment and OX40 blockade protect mice from acute and chronic virally-induced myocarditis. J Autoimmun 36:210-20
Van Belle, Tom L; Esplugues, Enric; Liao, Jeanette et al. (2011) Development of autoimmune diabetes in the absence of detectable IL-17A in a CD8-driven virally induced model. J Immunol 187:2915-22