Global transcriptional profiling demonstrates the combination of type I and type II interferon enhances antiviral and immune responses at clinically relevant doses.
A role for type II interferon (IFN-gamma) in resolving viral infection is suggested by the correlation of hepatitis C virus (HCV) clearance with enhancement of IFN-gamma-producing activated T cells in the resolution of acute HCV infection. Using vesicular stomatitis virus (VSV), a synergistic direct antiviral effect was documented using IFN-gamma1b and a potent, consensus type I IFN (IFN alfacon-1). Global expression profiling following EC50 exposure to IFN alfacon-1, IFN-gamma1b, or a cocktail of the two allowed the antiviral state to be correlated with induction of a subset of IFN-stimulated genes (ISGs). Genes identified through this analysis corresponded to classic antiviral components, ISGs more recently associated with direct antiviral functions, as well as expressed sequence tags (ESTs) and hypothetical proteins. The magnitude of these antiviral EC50-correlated expression events in human hepatoma (Huh7) cells exposed to clinically relevant doses of IFN alfacon-1, IFN-gamma1b, or a cocktail of the two was also probed because the standard of care for patients with chronic hepatitis C is type I IFN-containing regimens. Relative to type I IFNs used alone, the addition of type II IFN caused enhanced expression not only of many of the genes correlated with the direct antiviral state but also of genes involved in (1) antigen presentation to cytotoxic T lymphocytes (CTLs), (2) macrophage, natural killer (NK), and T helper 1 (Th1) cell recruitment and activation, (3) complement system function, (4) apoptosis, and (5) ISGs with unknown functions. As many of these processes are correlated clinically with resolution of chronic HCV infection, the combined use of these IFNs could display a beneficial effect on viral clearance in patients infected with HCV and other viruses through enhancement of one of these processes or of the direct antiviral state.
Tan
Hua
H
InterMune Inc., Brisbane, CA 94005, USA.
Derrick
Jena
J
Hong
Jin
J
Sanda
Corneliu
C
Grosse
William M
WM
Edenberg
Howard J
HJ
Taylor
Milton
M
Seiwert
Scott
S
Blatt
Lawrence M
LM
D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D016174:Hepacivirus / Q000276:immunology / Q000378:metabolism*; D006526:Hepatitis C / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism / Q000821:virology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011994:Recombinant Proteins
D000998:Antiviral Agents; D007370:Interferon Type I; D011994:Recombinant Proteins; D007371:Interferon-gamma