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J Virol, March 1998, p. 2246-2252, Vol. 72, No. 3
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Targeting a Polyepitope Protein Incorporating Multiple Class II-Restricted Viral Epitopes to the Secretory/Endocytic Pathway Facilitates Immune Recognition by CD4+ Cytotoxic T Lymphocytes: a Novel Approach to Vaccine Design

Scott A. Thomson,1 Scott R. Burrows,1 Ihor S. Misko,1 Denis J. Moss,1 Barbara E. H. Coupar,2 and Rajiv Khanna1,3,*

CRC for Vaccine Technology1 and Tumour Immunology Laboratory, EBV Unit,3 Queensland Institute of Medical Research, The Bancroft Centre, Brisbane 4006, and CSIRO, Australian Animal Health Laboratory, Geelong, Victoria,2 Australia

Received 11 August 1997/Accepted 20 November 1997

The role of CD4+ and CD8+ cells in the generation of an effective immune response against viral infections is well established. Moreover, there is an increasing realization that subunit vaccines which include both CD4+- and CD8+-T-cell epitopes are highly effective in controlling viral infections, as opposed to those which are designed to activate a CD8+- or CD4+-T-cell response alone. One of the major limitations of epitope-based vaccines designed to stimulate virus-specific CD4+ T cells is that endogenously expressed class II-restricted minimal cytotoxic-T-lymphocyte (CTL) epitopes are poorly recognized by CD4+ CTLs. In the present study we attempted to enhance the efficiency of class II-restricted endogenous presentation of minimal class II-restricted CTL epitopes by specifically targeting a polyepitope protein to class II processing compartments through the endosomal and/or lysosomal pathway. A significantly enhanced stimulation of virus-specific CD4+-T-cell clones by antigen-presenting cells (APC) expressing the recombinant polyepitope protein targeted to the endocytic/secretory pathway was readily demonstrated in cytotoxicity assays. In addition, in vitro activation of Epstein-Barr virus- and influenza virus-specific CD4+ memory CTLs by the recombinant constructs encoding the polyepitope protein, specifically targeted to the lysosomal compartment, was also demonstrated. The enhanced stimulatory capacity of APC expressing a lysosome-targeted polyepitope protein has important implications for vaccine design.

* Corresponding author. Mailing address: Queensland Institute of Medical Research, Bancroft Centre, 300 Herston Rd., Brisbane, Australia 4006. Phone: 61-7-3362 0346. Fax: 61-7-3362 0106. E-mail: rajivK{at}qimr.edu.au.




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