Abstract

Hepatitis C virus (HCV) infects over 150 million people worldwide. Interferon (IFN)-based therapy is the mainstay platform for treatment of HCV wherein improving IFN response rates remains paramount to achieving global sustained virological response. Genome-wide association studies (GWAS) have identified three single nucleotide polymorphisms (SNPs) near the interferon lambda 3 (IFNL3 also known as IL28B) gene that strongly associate with HCV patient response to therapy and natural clearance of infection. However, the functional polymorphism mediating these associations is still unknown. We have found that a 3'UTR polymorphism (rs4803217) dictates IFNL3 expression by altering mRNA stability through the recruitment of HCV-induced microRNAs (miRNAs) and AU-rich element (ARE)-binding proteins (ARE-BP). Our preliminary data show that expression of the rs4803217 T variant is repressed by the induced miRNAs and AU-rich element mediated decay, whereas a single T>G polymorphism rescues this suppression. This proposal aims to identify the specific ARE sequences and ARE-BP that function with miRNAs in the post-transcriptional regulon acting on IFNL3 variants. We will study the pathways that influence this regulon, namely the ability of HCV to induce host miRNAs in hepatocytes. Finally, we will investigate how the IFNL3 regulon affects the interferon-mediated antiviral response to HCV. This proposal will likely identify new therapeutic targets that can be manipulated in order to control HCV infection.

Public Health Relevance

Interferon (IFN) based combination therapy remains as the mainstay platform for treatment of HCV wherein improving IFN response rates remains paramount to achieving global sustainable virological response. We are investigating the post-transcriptional regulation of interferon lambda genes which are critical to clearance of HCV infection. Outcomes from the study outlined in this proposal will likely provide new therapeutic targets that can be manipulated in order to control HCV infection.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI108765-03
Application #
8990447
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Koshy, Rajen
Project Start
2014-01-01
Project End
2018-12-31
Budget Start
2016-01-01
Budget End
2016-12-31
Support Year
3
Fiscal Year
2016
Total Cost
$435,000
Indirect Cost
$185,000

  Institution

Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Hemann, Emily A; Gale Jr, Michael; Savan, Ram (2017) Interferon Lambda Genetics and Biology in Regulation of Viral Control. Front Immunol 8:1707
Forero, Adriana; So, Lomon; Savan, Ram (2017) Re-evaluating Strategies to Define the Immunoregulatory Roles of miRNAs. Trends Immunol 38:558-566
Hemann, Emily A; Schwerk, Johannes; Savan, Ram (2017) IFN-? 'guts' neutrophil-mediated inflammation. Nat Immunol 18:1061-1062
Jarret, Abigail; McFarland, Adelle P; Horner, Stacy M et al. (2016) Hepatitis-C-virus-induced microRNAs dampen interferon-mediated antiviral signaling. Nat Med 22:1475-1481
Hong, MeeAe; Schwerk, Johannes; Lim, Chrissie et al. (2016) Interferon lambda 4 expression is suppressed by the host during viral infection. J Exp Med 213:2539-2552
Schwerk, Johannes; Savan, Ram (2015) Translating the Untranslated Region. J Immunol 195:2963-71
Schwerk, Johannes; Jarret, Abigail P; Joslyn, Rochelle C et al. (2015) Landscape of post-transcriptional gene regulation during hepatitis C virus infection. Curr Opin Virol 12:75-84
Savan, Ram (2014) Post-transcriptional regulation of interferons and their signaling pathways. J Interferon Cytokine Res 34:318-29