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Circulating Tregs Correlate with Viral Load Reduction in Chronic HBV-Treated Patients with Tenofovir Disoproxil Fumarate

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Abstract

Limited response to current hepatitis B virus (HBV) drugs is possibly due to inadequate host cytotoxic cellular responses. Circulating Tregs have been shown to be associated with chronicity of HBV infection, but their profile during antiviral therapy has not been studied. We analyzed the frequency and effect of Tregs on cellular immune responses against HBV in 35 chronic hepatitis B eAg−ve and eAg+ve patients treated with tenofovir 300 mg/day. Frequency of Tregs and their modulatory role in cytokine-secreting cells were determined after stimulation with HBsAg or HBcAg in the absence or presence of Tregs and after blockage of PD-1/PDL-1 in peripheral blood mononuclear cells (PBMCs). Prior to therapy, eAg−ve patients had lower HBV DNA levels, reduced CD8 T cells, increased Tregs, and T cells expressing PD1. After 12 weeks of therapy, >2 log HBV viral reduction was observed in both groups, along with an increase frequencies of CD8 T cells in eAg−ve patients and increased expression of chemokine receptors/Toll-like receptors in both groups. PD-1 expression on CD8 cells in PBMCs was decreased in both groups during therapy but not on Tregs. In eAg–ve group, sustained increase of Tregs was observed till week 12, which declined at week 24. In both groups, after 24 weeks, depletion of CD4+CD25+ Tregs from PBMCs enhanced HBV-specific T cell responses, and blockage of PD-1/PDL1 pathway did enhance pro-inflammatory cytokine production in eAg+ve patients but not in eAg−ve. We conclude that Tregs induced by HBV replication in vivo are expanded in eAg−ve patients more. Reduction in HBV DNA by tenofovir partially restored adaptive immune responses and also reduced the Tregs. Blockage of PD-1/PDL1, enhanced cytokine production in eAg+ve patients but not in eAg−ve, suggests that distinctly different immunologic mechanisms are involved in eAg+ve and eAg−ve patients.

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Acknowledgments

This study was in part supported by grant no. BT/PR10283/GBD/27/91/2007 received from Department of Biotechnology, Govt. of India, New Delhi, India and by the intramural program of the National Institute of Allergy and Infectious Diseases, National Institute of Health (USA).

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Authors and Affiliations

  1. Institute of Liver and Biliary Sciences (ILBS), D-1, Vasant Kunj, New Delhi, 110 070, India

    Nirupma TrehanPati & Shiv Kumar Sarin

  2. Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India

    Nirupma TrehanPati, Syed S. Hissar, Shikha Shrivastava, Arshi Khanam, Sukriti Sukriti, Siddartha K. Mishra & Shiv Kumar Sarin

  3. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    Shyam Kotillil

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  1. Nirupma TrehanPati
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TrehanPati, N., Kotillil, S., Hissar, S.S. et al. Circulating Tregs Correlate with Viral Load Reduction in Chronic HBV-Treated Patients with Tenofovir Disoproxil Fumarate. J Clin Immunol 31, 509–520 (2011). https://doi.org/10.1007/s10875-011-9509-7

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