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Journal of Virology, December 2001, p. 11392-11400, Vol. 75, No. 23
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.23.11392-11400.2001

Cross-Reactivity between Hepatitis C Virus and Influenza A Virus Determinant-Specific Cytotoxic T Cells

Heiner Wedemeyer,1,dagger Eishiro Mizukoshi,1 Anthony R. Davis,1 Jack R. Bennink,2 and Barbara Rehermann1,*

Liver Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases,1 and Viral Immunology Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases,2 National Institutes of Health, Bethesda, Maryland 20982

Received 8 May 2001/Accepted 20 August 2001

The cellular immune response contributes to viral clearance as well as to liver injury in acute and chronic hepatitis C virus (HCV) infection. An immunodominant determinant frequently recognized by liver-infiltrating and circulating CD8+ T cells of HCV-infected patients is the HCVNS3-1073 peptide CVNGVCWTV. Using a sensitive in vitro technique with HCV peptides and multiple cytokines, we were able to expand cytotoxic T cells specific for this determinant not only from the blood of 11 of 20 HCV-infected patients (55%) but also from the blood of 9 of 15 HCV-negative blood donors (60%), while a second HCV NS3 determinant was recognized only by HCV-infected patients and not by seronegative controls. The T-cell response of these healthy blood donors was mediated by memory T cells, which cross-reacted with a novel T-cell determinant of the A/PR/8/34 influenza A virus (IV) that is endogenously processed from the neuraminidase (NA) protein. Both the HCV NS3 and the IV NA peptide displayed a high degree of sequence homology, bound to the HLA-A2 molecule with high affinity, and were recognized by cytotoxic T lymphocytes with similar affinity (10-8 M). Using the HLA-A2-transgenic mouse model, we then demonstrated directly that HCV-specific T cells could be induced in vivo by IV infection. Splenocytes harvested from IV-infected mice at the peak of the primary response (day 7 effector cells) or following complete recovery (day 21 memory cells) recognized the HCV NS3 peptide, lysed peptide-pulsed target cells, and produced gamma interferon. These results exemplify that host responses to an infectious agent are influenced by cross-reactive memory cells induced by past exposure to heterologous viruses, which could have important consequences for vaccine development.

* Corresponding author. Mailing address: Liver Diseases Section, NIDDK, National Institutes of Health, Bldg. 10, Room 9B16, 10 Center Dr. MSC 1800, Bethesda, MD 20892-1800. Phone: (301) 402-7144. Fax: (301) 402-0491. E-mail: Rehermann{at}nih.gov.

dagger Present address: Department of Gastroenterology and Hepatology, Medizinische Hochschule, 30625 Hannover, Germany.

Journal of Virology, December 2001, p. 11392-11400, Vol. 75, No. 23
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.23.11392-11400.2001


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