Hepatitis C virus (HCV) is the most common cause of chronic viral hepatitis in the United States. HIV coinfection and African ancestry are associated with impaired response to current standard of care pegylated IFN-alpha/ribavirin (PegIFN/RBV) and PegIFN/RBV/protease inhibitor (PI) therapy. Mechanisms underlying these associations are not clear, though IL28B (IFN-gamma3) gene region SNP genotype likely accounts for half of the racial association and HIV-associated immune impairment likely accounts for the HIV association. IL28B genotype is thought to affect level of IL28B expression, though little else is known about the mechanism of action. Newer PI containing therapy has increased HCV genotype 1 sustained virologic response (SVR) rates to around 70%. However, the need to combine PIs with PegIFN/RBV means that response to PI containing therapy remains IFN-alpha and IL28B dependent. Moreover, difficult to treat population (including HIV and African descent) PegIFN/RBV/PI SVR rates are likely <60%, requiring innovative strategies. Therefore, investigation of the mechanism underlying HIV, race and IL28B genotype effect on PegIFN/RBV/PI therapy response is key to better predict therapy outcome, and identify improved therapies. IFN-alpha has many effects on cell function, including direct natural killer (NK) cell activation. NK cell inhibitory receptor KIR2DL3 in combination with its weaker binding ligand (HLA-C1) are associated with greater clearance of acute HCV infection, and expression of specific NK cell killer immunoglobulin like receptors (KIRs) are also associated with response to IFN-alpha therapy. NK cells therefore likely play a role in control of HCV. Our new data indicate greater CD16+56- NK subset IFN-alpha R expression correlates with greater IFN-alpha induced IFN- alpha signaling, predicts response to IFN-alpha based HCV therapy, and is racially and IL28B genotype associated. Plasmacytoid dendritic cells (pDC) produce IFN-alpha during viral infection, and directly activate NK cells. Lower pDC and NK subset frequency and responsiveness to IFN are present during HIV infection. Our previous data indicate impairment in both NK and pDC contribute to impaired pDC-NK interactions in HIV infection. Lower pDC numbers and function are also present during HCV infection. Whether defects present in each infection combine in impairing HCV-HIV co-infected host ability to control of HCV is not known. Additionally, whether IL28B genotype underlies racially disparate NK IFN-alphaR expression level and consequent signaling is unclear. We propose a novel model that lends mechanistic insight into IL-28B, race and HIV effects on IFN-alpha based HCV therapy response. Elucidation of this model is intended to identify better outcome predictors, improved therapy options for difficult to treat populations, an better understand host-virus interactions. In this application we will 1) Determine the effect of IL28B, race, and HIV infection on NK and pDC-NK mediated control of HCV replication in vitro;2) To identify the mechanism underlying HIV and HCV associated impairment in IFN dependent NK function;and 3) Determine whether IL28B associated IFN-alphaR expression and IFN-alpha dependent NK control of HCV in vitro is predictive of in vivo control of HCV during PegIFN/RBV/PI therapy for HCV in the setting of HCV and HCV-HIV infection.

Public Health Relevance

Infection with HCV is particularly prevalent in the veteran population. Roughly 80% of veterans are at sufficient risk as to qualify for screening, and approximately 10% are infected. Infection with HCV constitutes the most common cause of chronic hepatitis in the United States. Many infected patients develop cirrhosis and end stage liver disease. Despite PI enhanced SVR rates, the need to combine PIs with IFN-alpha/RBV means that response to recently approved direct acting antiviral (DAA) therapies remains IFN-alpha and IL28B dependent. Additionally, difficult to treat population (including HIV and African descent) PegIFN/RBV/PI SVR rates are likely <60%, requiring innovative strategies. Even if IFN-free DAA therapies become possible in the coming decade, difficult to treat, DAA resistant, subpopulations will likely still benefit from IF therapy and favorable IL28B genotype. Investigation of the mechanism underlying HIV, race and IL28B mediated modulation of IFN therapy response is key to identifying improved therapies.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX001894-01
Application #
8438728
Study Section
Infectious Diseases A (INFA)
Project Start
2013-07-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
Indirect Cost
Name
Louis Stokes Cleveland VA Medical Center
Department
Type
DUNS #
093016124
City
Cleveland
State
OH
Country
United States
Zip Code
44141
Judge, Chelsey J; Kostadinova, Lenche; Sherman, Kenneth E et al. (2017) CD56bright NK IL-7R? expression negatively associates with HCV level, and IL-7-induced NK function is impaired during HCV and HIV infections. J Leukoc Biol 102:171-184
Judge, Chelsey J; Sandberg, Johan K; Funderburg, Nicholas T et al. (2016) Brief Report: CD14brightCD16- monocytes and sCD14 level negatively associate with CD4-memory T-cell frequency and predict HCV-decline on therapy. J Acquir Immune Defic Syndr 73:258-262
Reyes-Avil├ęs, Elane; Kostadinova, Lenche; Rusterholtz, Anne et al. (2015) Presence of Rheumatoid Factor during Chronic HCV Infection Is Associated with Expansion of Mature Activated Memory B-Cells that Are Hypo-Responsive to B-Cell Receptor Stimulation and Persist during the Early Stage of IFN Free Therapy. PLoS One 10:e0144629
Judge, Chelsey J; Reyes-Aviles, Elane; Conry, Sara J et al. (2015) HBD-3 induces NK cell activation, IFN-? secretion and mDC dependent cytolytic function. Cell Immunol 297:61-8
Kambara, Hiroto; Niazi, Farshad; Kostadinova, Lenche et al. (2014) Negative regulation of the interferon response by an interferon-induced long non-coding RNA. Nucleic Acids Res 42:10668-80
Kambara, Hiroto; Gunawardane, Lalith; Zebrowski, Elizabeth et al. (2014) Regulation of Interferon-Stimulated Gene BST2 by a lncRNA Transcribed from a Shared Bidirectional Promoter. Front Immunol 5:676
Meng, Qinglai; Rani, M R Sandhya; Sugalski, Julia M et al. (2014) Natural cytotoxicity receptor-dependent natural killer cytolytic activity directed at hepatitis C Virus (HCV) is associated with liver inflammation, African American race, IL28B genotype, and response to pegylated interferon/ribavirin therapy in chronic H J Infect Dis 209:1591-601
Leeansyah, Edwin; Malone, David F G; Anthony, Donald D et al. (2013) Soluble biomarkers of HIV transmission, disease progression and comorbidities. Curr Opin HIV AIDS 8:117-24