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. 2015 Mar 1:13:77.
doi: 10.1186/s12967-015-0428-x.

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

Maria Libera Ascierto, Federica Bozzano, Davide Bedognetti, Francesco Marras, Cathy Schechterly, Kentaro Matsuura, Antonino Picciotto, Simona Marenco, Yingdong Zhao, Valeria DeGiorgi, Michele Sommariva, Lorenzo Moretta, Ena Wang, Harvey J Alter, Francesco M Marincola, Andrea De Maria

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

Maria Libera Ascierto et al. J Transl Med. .

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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Figures

Figure 1
Figure 1
Trascriptional profile of NK cells derived from HCV infected patients with diverging treatment response. A) PCA analysis conducted on whole gene dataset expressed by NK cells of Healthy Individuals (HD), baseline responders (SVR) and non-responders (NR) HCV-1 patients. B) Supervised cluster based on 476 genes derived from Student’s t Test (cut off p2 value ≤ 0.005, FC >1.5) SVR vs. NR.
Figure 2
Figure 2
Functional analysis conducted on genes differentially expressed in HCV patients with diverging treatment response. A) IPA analysis conducted on the 476 transcripts differentially expressed in SVR vs. NR patients showed in the top network that molecules involved in mRNA processing and protein synthesis (such as SRSF molecules) are up regulated (in red) in SVR samples. B) Top 5 significant ranking significant (threshold p value < 0.05) canonical pathways conducted on the 476 transcripts reveled an up regulation of ubiquitination pathways as well as tRNA charging pathways in SVR patients. On the contrary, molecules involved in antigen presentation pathways are showed to be down regulated in SVR patients. The p value for each pathway is indicated by the blue bar and is expressed as –1 times the log of the p value. The yellow line represents the ratio of the number of genes in a given pathway that meet the cutoff criteria divided by the total number of genes that make up that pathway.
Figure 3
Figure 3
Correlation of activating NK cell receptor (NKp30 and NKG2D) expression with divergent treatment responses during HCV infection. A) Representation of gating strategy adopted for the evaluation of NKp30 and NKG2D expression in the CD56 + CD3-CD19-CD14- PBMCs derived from training SVR and NR patients. B) Further correlation (Mann Whitney u test) with INFα + rivabirin treatment response showed a significant up regulation of NKp30 and NKG2D in NR. Results obtained for NKp30 confirmed previous observations [29].
Figure 4
Figure 4
The SVR: NR gene set transcriptional profile is validated in independent cohorts of HCV patients. A) PCA analysis performed on the independent group of patients by using the 476 genes associated with treatment response in the training set of patients; B) PCA analysis performed on 8 treatment naïve chronically infected HCV patients (CH-HCV) by using the 476-transcript signature segregated the CH-HCV patients according a SVR-like and NR-like. Because of the high heterogeneity of NK profile derived from NR-like patients, the PCA was conducted by adding a centroid for each group of patients. C) The expression of NKp30 and NKG2D was evaluated on purified NK cells showing to be higher in NR-like patients as previously reported to occur for NR patients [29,34].
Figure 5
Figure 5
Analysis of pre-treatment NK cells trascriptome according to the level of HCV viremia. A) Supervised cluster based on 165 genes derived from Student’s t Test Chronic Viraemic HCV patients (CV-HCV) vs. HD (Cut off p value <0.005; FC > 1.5). B) Venn diagram between the 476 genes able to differentiate NR vs. SVR patients and the 165 genes associated with viremia. Among the genes able to segregate the SVR from the NR, only 22 genes (5%) were affected by viremia.
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