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Journal of Virology, May 2005, p. 5529-5536, Vol. 79, No. 9
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.9.5529-5536.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Cross-Reactive Cytotoxic T Lymphocytes against Human Immunodeficiency Virus Type 1 Protease and Gamma Interferon-Inducible Protein 30

R. D. Mason,1 M. I. Bowmer,2 C. M. Howley,2 and M. D. Grant1*

Immunology Program, Division of Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland,1 St. John's Health Care Corporation, St. John's, Newfoundland, Canada2

Received 9 September 2004/ Accepted 16 December 2004

The gamma interferon (IFN-{gamma})-inducible protein 30 (IP-30) signal peptide –11 to –3 (LLDVPTAAV) is a prominent self peptide expressed with the class I human histocompatibility leukocyte antigen A2 (HLA-A2). Stimulation of peripheral blood mononuclear cells (PBMC) from HLA-A2 human immunodeficiency virus type 1 (HIV-1)-infected individuals with an HLA-A2-restricted HIV protease (PR) peptide 76-84 (LVGPTPVNI) activated cytotoxic T lymphocytes (CTL) against the IP-30 signal peptide. Since HIV-1 PR 76-84 stimulated CD8+ T cells from these individuals to secrete IFN-{gamma}, we tested whether the activation of IP-30-specific CTL in vitro resulted from T-cell cross-reactivity or from up-regulation of IP-30 by IFN-{gamma}. Neither high levels of exogenous IFN-{gamma} nor incubation of PBMC with other HIV peptides triggering substantial IFN-{gamma} release activated IP-30-specific CTL. Although the IP-30 signal peptide did not stimulate IFN-{gamma} release from freshly isolated PBMC, it activated CTL in vitro against itself and HIV PR 76-84. Peptide-stimulated IFN-{gamma} release, cold target inhibition, and HLA-A2/immunoglobulin dimer-mediated binding and depletion of effector cells all indicated that in vitro stimulation with HIV PR 76-84 or the IP-30 signal peptide activated a comparable population of cross-reactive effector cells. Neither IP-30 nor HIV PR 76-84 activated CTL against themselves following in vitro stimulation of PBMC from non-HIV-infected HLA-A2 individuals. Peptide titrations indicated higher-avidity T-cell interactions with HIV PR 76-84 than with the IP-30 signal peptide. These data indicate that HIV PR 76-84 is a heteroclitic variant of the IP-30 signal peptide –11 to –3, which has implications for immune memory and autoimmunity.

* Corresponding author. Mailing address: H1809 Immunology-Faculty of Medicine, Memorial University of Newfoundland, 300 Prince Philip Drive, St. John's, Newfoundland, Canada A1B 3V6. Phone: (709) 777-8292. Fax: (709) 777-8294. E-mail: mgrant{at}mun.ca.

Journal of Virology, May 2005, p. 5529-5536, Vol. 79, No. 9
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.9.5529-5536.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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