T cell immunity is crucial to control viral infection and prevent persistence. However, T cell functions are rapidly aborted during persistent infection, preventing viral clearance. Mounting evidence indicates that CD4 T cell helper responses are required to sustain immune competence and that the loss of CD4 T cell function is a key event permitting viral persistence. Many of the functional characteristics of CDS T cell exhaustion (failure to sustain activity, proliferate, develop memory) can potentially be explained by the loss of CD4 help. Despite immune exhaustion some persistent viral infections are eventually resolved via unknown CD4 T cell dependent mechanisms, suggesting that CD4 T cells retain helper function during viral persistence. Recently, we discovered that upregulation of IL-21 by CD4 T cells is absolutely required to sustain antiviral immunity and resolve an established persistent viral infection. The goal of this application is to understand how CD4 T cell help is altered during viral persistence and ultimately to identify the IL-21 mediated mechanisms that sustain immunity. To achieve this goal we will use the mouse model of lymphocytic choriomeningitis virus (LCMV) infection to explore virus-specific CD4 T helper differentiation during viral persistence and how IL-21 directs this developmental program. Next, we will define the mechanism whereby IL-21 simultaneously suppresses CD4 T cell mediated immunopathology and sustains CDS T cell immunity to resolve persistent viral infection. These studies will investigate a novel mechanism of CD4 T cell help during viral persistence (at a time when CD4 T cell function was previously considered lost) and will be the first to identify the immune components that resolve an established persistent viral infection. It is important to identify the mechanisms that alternatively sustain and suppress antiviral immunity to develop therapies to restore T cell function and potentially cure persistent infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI082975-05
Application #
8462531
Study Section
Special Emphasis Panel (ZAI1-BDP-I (J4))
Program Officer
Miller, Lara R
Project Start
2009-05-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$379,140
Indirect Cost
$132,945
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
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
Ng, Cherie T; Snell, Laura M; Brooks, David G et al. (2013) Networking at the level of host immunity: immune cell interactions during persistent viral infections. Cell Host Microbe 13:652-64
Wilson, Elizabeth B; Brooks, David G (2013) Decoding the complexity of type I interferon to treat persistent viral infections. Trends Microbiol 21:634-40
Wilson, Elizabeth B; Yamada, Douglas H; Elsaesser, Heidi et al. (2013) Blockade of chronic type I interferon signaling to control persistent LCMV infection. Science 340:202-7
Wilson, Elizabeth B; Brooks, David G (2013) Inflammation makes T cells sensitive. Immunity 38:5-7
Fahey, Laura M; Wilson, Elizabeth B; Elsaesser, Heidi et al. (2011) Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells. J Exp Med 208:987-99
Wilson, Elizabeth B; Brooks, David G (2011) The role of IL-10 in regulating immunity to persistent viral infections. Curr Top Microbiol Immunol 350:39-65
Fahey, Laura M; Brooks, David G (2010) Opposing positive and negative regulation of T cell activity during viral persistence. Curr Opin Immunol 22:348-54
Brooks, David G; Walsh, Kevin B; Elsaesser, Heidi et al. (2010) IL-10 directly suppresses CD4 but not CD8 T cell effector and memory responses following acute viral infection. Proc Natl Acad Sci U S A 107:3018-23
Wilson, Elizabeth B; Brooks, David G (2010) Translating insights from persistent LCMV infection into anti-HIV immunity. Immunol Res 48:3-13

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