Persistent viral infections are a worldwide health concern, with over 500 million people infected with HIV and hepatitis B and C viruses (HBV, HCV). By definition, immune escape is required for viral persistence;however the suppressive mechanisms that abort immunity during persistent viral infections are not well defined. T cell responses are crucial to prevent and control viral infections. Although robust T cell responses are initially mounted to these viruses, T cells rapidly lose activity permitting persistence. Recent evidence suggests that the functionally non-responsive T cell state (exhaustion) is not programmed during T cell activation, but that T cell responses are actively suppressed throughout infection. We discovered that infection with a persistent strain of lymphocytic choriomeningitis virus (LCMV) triggers high IL-10 production that directly ablates T cell function and causes viral persistence. Antibody blockade of IL-10 restored T cell activity and purged the persistent infection, indicating that host regulatory mechanisms actually permit viral persistence and are actively responsible for preventing clearance. This research suggests the exciting prospect that, when freed, T cells are capable of controlling persistent viruses. A better understanding of how immunosuppressive factors inhibit immunity is critical for the design of therapies to re-establish immune control and prevent and potentially eradicate persistent viral infections. In the current proposal I will define the mechanisms leading to IL-10 mediated immunosuppression during persistent viral infection. I will utilize cutting- edge microscopy techniques to directly visualize immunosuppressive cells in vivo and the specific interactions that suppress T cell function and sustain T cell exhaustion. These studies will provide the first in vivo mechanistic insights into how host molecules cause immunosuppression during persistent viral infection. I will then test a novel strategy to enhance T cell immunity and purge a long- lived reservoir of viral replication from an immune privileged site. Once completed this effort will have a direct impact toward our understanding of host-virus interactions, the mechanisms employed to promote viral clearance versus persistence and therapeutically the ability to restore immune function to completely eliminate persistent infection.

Public Health Relevance

Strategies to enhance immune activity to clear persistent viral infections have so far been unsuccessful because it is unclear what is required of the immune response to purge virus once it proceeds past acute infection. The experiments outlined in this proposal will investigate a novel factor required to clear a persistent viral infection. Identification of the mechanisms that sustain immunity will aid in the design of therapies to amplify the immune response to control persistent viral infections

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI085043-03
Application #
8197096
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Lapham, Cheryl K
Project Start
2009-12-01
Project End
2014-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
3
Fiscal Year
2012
Total Cost
$376,165
Indirect Cost
$128,665
Name
University of California Los Angeles
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Zhen, Anjie; Rezek, Valerie; Youn, Cindy et al. (2017) Targeting type I interferon-mediated activation restores immune function in chronic HIV infection. J Clin Invest 127:260-268
Clemente-Casares, Xavier; Hosseinzadeh, Siyavash; Barbu, Iulia et al. (2017) A CD103+ Conventional Dendritic Cell Surveillance System Prevents Development of Overt Heart Failure during Subclinical Viral Myocarditis. Immunity 47:974-989.e8
Cunningham, Cameron R; Champhekar, Ameya; Tullius, Michael V et al. (2016) Type I and Type II Interferon Coordinately Regulate Suppressive Dendritic Cell Fate and Function during Viral Persistence. PLoS Pathog 12:e1005356
Snell, Laura M; Osokine, Ivan; Yamada, Douglas H et al. (2016) Overcoming CD4 Th1 Cell Fate Restrictions to Sustain Antiviral CD8 T Cells and Control Persistent Virus Infection. Cell Rep 16:3286-3296
York, Autumn G; Williams, Kevin J; Argus, Joseph P et al. (2015) Limiting Cholesterol Biosynthetic Flux Spontaneously Engages Type I IFN Signaling. Cell 163:1716-29
Snell, Laura M; Brooks, David G (2015) New insights into type I interferon and the immunopathogenesis of persistent viral infections. Curr Opin Immunol 34:91-8
Yamada, Douglas H; Elsaesser, Heidi; Lux, Anja et al. (2015) Suppression of Fc?-receptor-mediated antibody effector function during persistent viral infection. Immunity 42:379-390
Walsh, Nicole C; Waters, Lynnea R; Fowler, Jessica A et al. (2015) LKB1 inhibition of NF-?B in B cells prevents T follicular helper cell differentiation and germinal center formation. EMBO Rep 16:753-68
Osokine, Ivan; Snell, Laura M; Cunningham, Cameron R et al. (2014) Type I interferon suppresses de novo virus-specific CD4 Th1 immunity during an established persistent viral infection. Proc Natl Acad Sci U S A 111:7409-14
Wilson, Elizabeth B; Brooks, David G (2013) Decoding the complexity of type I interferon to treat persistent viral infections. Trends Microbiol 21:634-40

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