Mechanisms of Viral Persistence

Information

  • Research Project
  • 9420509
  • ApplicationId
    9420509
  • Core Project Number
    R01AI085043
  • Full Project Number
    5R01AI085043-10
  • Serial Number
    085043
  • FOA Number
    PA-13-302
  • Sub Project Id
  • Project Start Date
    12/1/2009 - 14 years ago
  • Project End Date
    1/31/2020 - 4 years ago
  • Program Officer Name
    SINGLETON, KENTNER L
  • Budget Start Date
    2/1/2018 - 6 years ago
  • Budget End Date
    1/31/2019 - 5 years ago
  • Fiscal Year
    2018
  • Support Year
    10
  • Suffix
  • Award Notice Date
    1/23/2018 - 6 years ago

Mechanisms of Viral Persistence

? DESCRIPTION (provided by applicant): Persistent viral infections are among the greatest health concerns worldwide. By definition, immune escape is required for viral persistence, and many of the suppressive factors involved are being identified. Yet, it is still unclear how prolonged virus replication leads to the expression of the many and mechanistically diverse suppressive factors, pathways and cells that inhibit immunity during persistent viral infections. Type I interferons (IFN-I) are well known for their antiviral activity during virus infection. However, using the lymphocytic choriomeningitis virus (LCMV) system, we discovered that in addition to their critical antiviral role throughout viral persistence, sustained IFN-I production ed to many of the suppressive mechanisms and immune dysfunctions associated with persistent viral infections. Antibody blockade of IFN-I signaling decreased immunosuppression, restored immune competence and facilitated immune mediated control of the persistent infection. In the current proposal, we will mechanistically define how IFN-I functions as the mediator of the multiple and diverse parameters of immunosuppression that ultimately potentiate viral persistence. We will then test the hypothesis that the distinct antiviral and suppressive aspects of IFN-I signaling can be uncoupled to specifically inhibit the negative while maintaining the critical positive functions of IFN-I to restore immunity and control infection. These studies will provide critical biologic insight into how IFN-I simultaneously induces antiviral and suppressive functions and will potentially guide the way we therapeutically target IFN-I to treat disease. Finally, we will investigate a novel IFN-I induced mechanism of immunosuppression to define how IFN-I implements secondary down-stream effectors to promote viral persistence. Ultimately, our study will provide fundamental insight into a new aspect of IFN-I biology and facilitate the first understanding of a newly described mechanism of immunosuppression potentiating viral persistence.

IC Name
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
  • Activity
    R01
  • Administering IC
    AI
  • Application Type
    5
  • Direct Cost Amount
    250000
  • Indirect Cost Amount
    20000
  • Total Cost
    270000
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    855
  • Ed Inst. Type
  • Funding ICs
    NIAID:270000\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    IHD
  • Study Section Name
    Immunity and Host Defense
  • Organization Name
    UNIVERSITY HEALTH NETWORK
  • Organization Department
  • Organization DUNS
    208469486
  • Organization City
    TORONTO
  • Organization State
    ON
  • Organization Country
    CANADA
  • Organization Zip Code
    M5G 2M9
  • Organization District
    CANADA