Inherent transcriptional signatures of NK cells are associated with response to IFNα + rivabirin therapy in patients with Hepatitis C Virus

• Published in: Journal of translational medicine Vol. 13; no. 1; p. 77
• Main Authors: Ascierto, Maria Libera, Bozzano, Federica, Bedognetti, Davide, Marras, Francesco, Schechterly, Cathy, Matsuura, Kentaro, Picciotto, Antonino, Marenco, Simona, Zhao, Yingdong, DeGiorgi, Valeria, Sommariva, Michele, Moretta, Lorenzo, Wang, Ena, Alter, Harvey J, Marincola, Francesco M, De Maria, Andrea
• Format: Journal Article
• Language: English
• Published: England BioMed Central 01.03.2015
• Subjects: Cohort Studies; Gene Expression Profiling; Hepacivirus - drug effects; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - genetics; Humans; Interferon-alpha - pharmacology; Interferon-alpha - therapeutic use; Interferons; Interleukins - genetics; Killer Cells, Natural - drug effects; Killer Cells, Natural - metabolism; Natural Cytotoxicity Triggering Receptor 3 - metabolism; NK Cell Lectin-Like Receptor Subfamily K - metabolism; Polymorphism, Single Nucleotide - genetics; Reproducibility of Results; Ribavirin - pharmacology; Ribavirin - therapeutic use; Transcription, Genetic - drug effects; Treatment Outcome
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-015-0428-x

Differences in the expression of Natural Killer cell receptors have been reported to reflect divergent clinical courses in patients with chronic infections or tumors. However, extensive molecular characterization at the transcriptional level to support this view is lacking. The aim of this work was to characterize baseline differences in purified NK cell transcriptional activity stratified by response to treatment with PEG-IFNα/RBV in patients chronically infected with HCV. To this end we here studied by flow cytometer and gene expression profile, phenotypic and transcriptional characteristics of purified NK cells in patients chronically infected with HCV genotype-1 virus who were subsequently treated with PEG-IFNα/RBV. Results were further correlated with divergent clinical response obtained after treatment. The pre-treatment transcriptional patterns of purified NK cells from patients subsequently undergoing a sustained virologic response (SVR) clearly segregated from those of non-responder (NR) patients. A set of 476 transcripts, including molecules involved in RNA processing, ubiquitination pathways as well as HLA class II signalling were differently expressed among divergent patients. In addition, treatment outcome was associated with differences in surface expression of NKp30 and NKG2D. A complex relationship was observed that suggested for extensive post-transcriptional editing. Only a small number of the NK cell transcripts identified were correlated with chronic HCV infection/replication indicating that inherent transcriptional activity prevails over environment effects such as viral infection. Collectively, inherent/genetic modulation of NK cell transcription is involved in setting the path to divergent treatment outcomes and could become useful to therapeutic advantage.