, Volume 20, Issue 4, pp 466–480 | Cite as

Chronic hepatitis C virus infection triggers spontaneous differential expression of biosignatures associated with T cell exhaustion and apoptosis signaling in peripheral blood mononucleocytes

  • Muttiah Barathan
  • Kaliappan Gopal
  • Rosmawati Mohamed
  • Rada Ellegård
  • Alireza Saeidi
  • Jamuna Vadivelu
  • Abdul W. Ansari
  • Hussin A. Rothan
  • M. Ravishankar Ram
  • Keivan Zandi
  • Li Y. Chang
  • Ramachandran Vignesh
  • Karlhans F. Che
  • Adeeba Kamarulzaman
  • Vijayakumar Velu
  • Marie Larsson
  • Tunku Kamarul
  • Esaki M. ShankarEmail author
Original Paper


Persistent hepatitis C virus (HCV) infection appears to trigger the onset of immune exhaustion to potentially assist viral persistence in the host, eventually leading to hepatocellular carcinoma. The role of HCV on the spontaneous expression of markers suggestive of immune exhaustion and spontaneous apoptosis in immune cells of chronic HCV (CHC) disease largely remain elusive. We investigated the peripheral blood mononuclear cells of CHC patients to determine the spontaneous recruitment of cellular reactive oxygen species (cROS), immunoregulatory and exhaustion markers relative to healthy controls. Using a commercial QuantiGenePlex® 2.0 assay, we determined the spontaneous expression profile of 80 different pro- and anti-apoptotic genes in persistent HCV disease. Onset of spontaneous apoptosis significantly correlated with the up-regulation of cROS, indoleamine 2,3-dioxygenase (IDO), cyclooxygenase-2/prostaglandin H synthase (COX-2/PGHS), Foxp3, Dtx1, Blimp1, Lag3 and Cd160. Besides, spontaneous differential surface protein expression suggestive of T cell inhibition viz., TRAIL, TIM-3, PD-1 and BTLA on CD4+ and CD8+ T cells, and CTLA-4 on CD4+ T cells was also evident. Increased up-regulation of Tnf, Tp73, Casp14, Tnfrsf11b, Bik and Birc8 was observed, whereas FasLG, Fas, Ripk2, Casp3, Dapk1, Tnfrsf21, and Cflar were moderately up-regulated in HCV-infected subjects. Our observation suggests the spontaneous onset of apoptosis signaling and T cell exhaustion in chronic HCV disease.


Apoptosis Caspase Hepatitis C Spontaneous immune exhaustion TRAIL 



We thank all the participants, clinical, paraclinical and laboratory staff of University of Malaya Medical Center for assistance with patient recruitment, specimen collection and cooperation. This work was financially supported by the High Impact Research (UM.C.625/1/HIR/139), University of Malaya to Esaki M. Shankar for a study titled ‘Mechanisms of T cell dysfunctions in hepatitis C infection’. Tunku Kamarul is supported by the HIRG-MOHE A000003-50001 Grant of University of Malaya. Marie Larsson is supported by Grant No. AI52731 from the Swedish Research Council, the Swedish Physicians against AIDS Research Foundation, the Swedish International Development Cooperation Agency; SIDA SARC, VINNMER for Vinnova, Linköping University Hospital Research Fund, CALF and the Swedish Society of Medicine. We also acknowledge financial support from the University of Malaya Research Grant (UMRG) RG448-12HTM of the Health and Translational Medicine Research Cluster, University of Malaya to Esaki M. Shankar.

Conflict of interest

The authors declare that they have no conflict of interest to disclose.


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Muttiah Barathan
    • 1
  • Kaliappan Gopal
    • 2
  • Rosmawati Mohamed
    • 3
  • Rada Ellegård
    • 4
  • Alireza Saeidi
    • 1
  • Jamuna Vadivelu
    • 1
  • Abdul W. Ansari
    • 5
  • Hussin A. Rothan
    • 6
  • M. Ravishankar Ram
    • 1
  • Keivan Zandi
    • 1
  • Li Y. Chang
    • 1
  • Ramachandran Vignesh
    • 7
  • Karlhans F. Che
    • 8
  • Adeeba Kamarulzaman
    • 3
    • 5
  • Vijayakumar Velu
    • 9
  • Marie Larsson
    • 4
  • Tunku Kamarul
    • 2
  • Esaki M. Shankar
    • 1
    • 5
    Email author
  1. 1.Tropical Infectious Disease Research and Education Center (TIDREC), Department of Medical Microbiology, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
  2. 2.National Orthopedics Center for Excellence in Research and Learning (NOCERAL), Department of Orthopedics surgery, Tissue engineering group (TEG), Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
  3. 3.Department of MedicineUniversity of MalayaKuala LumpurMalaysia
  4. 4.Division of Molecular Virology, Department of Clinical and Experimental MedicineLinköping UniversityLinköpingSweden
  5. 5.Center for of Excellence for Research in AIDS (CERiA)University of MalayaKuala LumpurMalaysia
  6. 6.Department of Molecular MedicineUniversity of MalayaKuala LumpurMalaysia
  7. 7.YRG Center for AIDS Research and EducationVoluntary Health Services Hospital CampusChennaiIndia
  8. 8.Unit for Lung and Airway Research, Division of Physiology, Institute for Environmental MedicineKarolinska InstituteStockholmSweden
  9. 9.Department of Microbiology and ImmunologyEmory Vaccine CenterAtlantaUSA

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