Persistent (chronic) viral infections of humans afflict more than 500 million people. A diminished role for dendritic cell (DC) function in generating antiviral T and B lymphocytes, coupled with a functional loss (exhaustion, hyporesponsiveness) in antiviral T cells observed in persistent infections results in the inability of the host to remoe infected cells the factories harboring and producing virus. Although each virus has its own unique signature, the premiere experimental model for study, analysis and obtaining strategies to control persistent viral infections is lymphocytic choriomeningitis virus (LCMV) infection in it murine host. Use of this in vivo model provided the initial evidence that generation of negative regulators of the immune response like IL-10 and PD-1 that were responsible for suppressing the antiviral immune response leading to T cell exhaustion, events that were later and quickly extended to persistent human viral infections like HIV, HCV, and HBV. Our laboratory, with funds from this grant, provided the evidence for IL-10 and its production by DCs. IL- 10 is a key player in the establishment and maintenance of viral persistence as antibody neutralization of IL-10 receptor in vivo restores T cell function leading to purging of virus and elimination of the persistent infection. Utilizing reverse genetics we documented that only two amino acids in the LCMV variant Clone 13 decided if a persistent infection would occur in immunocompetent adult hosts compared to the original cloned LCMV source ARM 53b that does not persist. In the viral spike glycoprotein residue 260 (Cl 13/ARM: leu/phe) determines virus binding to its receptor, alpha-dystroglycan (?-DG) which is prominently displayed on DCs and is essential for viral entry. The second mutation in the polymerase gene (residue 1079 Cl 13/ARM: glu/lys) favors a 1.5 to 2 log higher replication in DCs, but not fibroblasts or other cells for LCMV possessing the Cl 13 polymerase gene. This grant proposes to uncover the molecular basis of how virus alters DC function and define how IL-10 causes persistence. Further, the grant also explores the exciting prospect of discovery and utilizing small molecule(s) that block both IL-10 and PD-1 as well as other negative regulators of the immune system induced by persisting viruses. We approach the problem of persistent infection by understanding the molecular and biologic mechanisms underlying virus/DC interactions and T cell exhaustion using the wealth of information, reagents and viruses we and others have generated. We plan to assay for potent, specific small molecules that can reverse the suppression of the virus-specific T cell response caused by both IL-10 and PD-1 thereby restoring antiviral immunity. We hypothesize that therapies for the treatment of viral persistence will result from the basic mechanistic and chemical discovery efforts currently underway. This proposal provides an integrated, multidisciplinary approach to evaluate the role of the virus, immune response and DC that already has proven its capabilities by defining novel mechanisms in viral pathogenesis and persistent viral infections.

Public Health Relevance

Persistent viral infections of humans (like HIV, HCV, and HBV) afflict more than 500 million people worldwide. A common thread in persistent viral infections is the functional loss (exhaustion/hypo- responsiveness) in activity of antiviral T and cells responsible for controlling and eliminating the infecting virus. Here we molecularly dissect the cause for the loss of antiviral T and B cell function and utilize a high output screen to obtai molecule(s) that will restore T and B cell function and hence terminate the persistent viral infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI009484-44A1
Application #
8492836
Study Section
Virology - B Study Section (VIRB)
Program Officer
Park, Eun-Chung
Project Start
1977-09-01
Project End
2017-04-30
Budget Start
2013-05-15
Budget End
2014-04-30
Support Year
44
Fiscal Year
2013
Total Cost
$445,325
Indirect Cost
$210,325
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Baccala, Roberto; Welch, Megan J; Gonzalez-Quintial, Rosana et al. (2014) Type I interferon is a therapeutic target for virus-induced lethal vascular damage. Proc Natl Acad Sci U S A 111:8925-30
Walsh, Kevin B; Teijaro, John R; Brock, Linda G et al. (2014) Animal model of respiratory syncytial virus: CD8+ T cells cause a cytokine storm that is chemically tractable by sphingosine-1-phosphate 1 receptor agonist therapy. J Virol 88:6281-93
Teijaro, John R; Walsh, Kevin B; Long, James P et al. (2014) Protection of ferrets from pulmonary injury due to H1N1 2009 influenza virus infection: immunopathology tractable by sphingosine-1-phosphate 1 receptor agonist therapy. Virology 452-453:152-7
Oldstone, Michael B A; Rosen, Hugh (2014) Cytokine storm plays a direct role in the morbidity and mortality from influenza virus infection and is chemically treatable with a single sphingosine-1-phosphate agonist molecule. Curr Top Microbiol Immunol 378:129-47

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