Chronic viral infections afflict more than 500 million people worldwide. Loss of T cell function has been noticed for long time during persistent viral infections but the underlying factors are not completely understood. By using in vivo chronic lymphocytic choriomeningitis virus (LCMV) infection in mice, we recently found that specific and exclusive attenuation of TGF? signaling on CD4 and CD8 T cells allows the generation of a powerful and functional T cell response in vivo. Remarkably, elimination of the virus is rapidly achieved and memory T cells emerge. These findings are significant and therapeutically relevant since the effects of reducing TGF? signaling are profound. However, understanding the cellular and molecular factors underlying the role of TGF? during viral persistence is essential for manipulating this pathway to boost anti-viral defense with minimal side effects. In this proposal, we plan to dissect TGF? biology in the context of a chronic viral infection. We will examine the cell source responsible for TGF? production as well as the factors regulating TGF? activation, a required step to expose the bioactive form of this molecule. We will also determine the direct and indirect effects of TGF? on CD4 and CD8 T cells and their link to other inhibitory pathways previously described. Finally, we will evaluate the potential of TGF? inhibition in vivo to eradicate an early-stage or fully established persistent infection. Our recent findings identify TGF? as a novel inhibitory molecule responsible for T cell exhaustion and viral persistence in vivo. These observations yield promising novel opportunities to be considered for devising new immunotherapies and deserve further study to harness the greatest potential of this pathway to cure or alleviate human chronic viral diseases without causing immunopathology.

Public Health Relevance

Viruses that cause chronic infections, including Human Immunodeficiency virus (HIV), Hepatitis B virus (HBV) and Hepatitis C virus (HCV), infect more than 500 million people worldwide and represent a major health problem. Progression to chronic phase has been associated with loss of T cell function (i.e. exhaustion) through multiple and conserved inhibitory pathways that appear to be shared between distinct chronic viral infections in different hosts. This proposal is focused on the study of a novel inhibitory pathway responsible for viral persistence in vivo, its contextual linkage with other known immunosuppressive pathways and its therapeutic potential for eradicating a chronic viral infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI081923-05
Application #
8493978
Study Section
Virology - B Study Section (VIRB)
Program Officer
Lapham, Cheryl K
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$374,790
Indirect Cost
$129,642
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Loureiro, MarĂ­a Eugenia; Zorzetto-Fernandes, Andre Luiz; Radoshitzky, Sheli et al. (2018) DDX3 suppresses type I interferons and favors viral replication during Arenavirus infection. PLoS Pathog 14:e1007125
Macal, Monica; Jo, Yeara; Dallari, Simone et al. (2018) Self-Renewal and Toll-like Receptor Signaling Sustain Exhausted Plasmacytoid Dendritic Cells during Chronic Viral Infection. Immunity 48:730-744.e5
Harker, James A; Wong, Kurt A; Dallari, Simone et al. (2018) Interleukin-27R Signaling Mediates Early Viral Containment and Impacts Innate and Adaptive Immunity after Chronic Lymphocytic Choriomeningitis Virus Infection. J Virol 92:
Wehrens, Ellen J; Wong, Kurt A; Gupta, Ankan et al. (2018) IL-27 regulates the number, function and cytotoxic program of antiviral CD4 T cells and promotes cytomegalovirus persistence. PLoS One 13:e0201249
Kakaradov, Boyko; Arsenio, Janilyn; Widjaja, Christella E et al. (2017) Early transcriptional and epigenetic regulation of CD8+ T cell differentiation revealed by single-cell RNA sequencing. Nat Immunol 18:422-432
Smelkinson, Margery G; Guichard, Annabel; Teijaro, John R et al. (2017) Influenza NS1 directly modulates Hedgehog signaling during infection. PLoS Pathog 13:e1006588
Macal, Monica; Tam, Miguel A; Hesser, Charles et al. (2016) CD28 Deficiency Enhances Type I IFN Production by Murine Plasmacytoid Dendritic Cells. J Immunol 196:1900-9
Lewis, Gavin M; Wehrens, Ellen J; Labarta-Bajo, Lara et al. (2016) TGF-? receptor maintains CD4 T helper cell identity during chronic viral infections. J Clin Invest 126:3799-3813
El Ghazal, Roland; Yin, Xin; Johns, Scott C et al. (2016) Glycan Sulfation Modulates Dendritic Cell Biology and Tumor Growth. Neoplasia 18:294-306
Taylor, Alison; Harker, James A; Chanthong, Kittiphat et al. (2016) Glycogen Synthase Kinase 3 Inactivation Drives T-bet-Mediated Downregulation of Co-receptor PD-1 to Enhance CD8(+) Cytolytic T Cell Responses. Immunity 44:274-86

Showing the most recent 10 out of 22 publications