[Frontiers in Bioscience 7, d1503-1515, June 1, 2002]

T-LYMPHOCYTE EPITOPE IDENTIFICATION AND THEIR USE IN VACCINE DEVELOPMENT FOR HIV-1

Mark J. Newman, Brian Livingston, Denise M. McKinney, Robert W. Chesnut and Alessandro Sette

Epimmune Inc., 5820 Nancy Ridge Drive, San Diego, CA 92121

TABLE OF CONTENTS

1. Abstract
2. Introduction
2.1. Correlation between T-lymphocyte responses and HIV-1 infection status or disease prognosis
2.1.1. T-lymphocyte responses in acutely infected individuals
2.1.2. T-lymphocyte responses in chronically-infected individuals
2.1.3. T-lymphocyte responses in exposed but uninfected individuals
2.1.4. Structured treatment interruptions (STI) as a method of increasing HIV-1 specific T-lymphocyte responses
3. T-lymphocyte epitopes
3.1. CTL epitope identification
3.2. HTL epitope identification
3.3. Direct measurement of epitope peptide binding to HLA-A, HLA-B and HLA-DR molecules
4. Identification and characterization of HIV-1 CTL and HTL epitopes
5. Design and development of vaccines composed of multiple epitopes
6.Optimization of CTL epitope vaccines
6.1. Avoiding the creation of junctional epitopes
6.2. Use of amino acid spacers to optimize epitope processing
7. Construction of multi-HTL epitope vaccines
8. Summary and Conclusions
9. Acknowledgments
10. References

1. ABSTRACT

Cellular immune responses mediated by CD8+ cytotoxic T-lymphocytes (CTL) and CD4+ helper T-lymphocytes (HTL) are needed to effectively control and clear many viral pathogens, including HIV-1. Thus, vaccines for HIV-1 capable of inducing CTL and HTL responses are now the focus of multiple academic and industry-based research and development programs. The use of defined, minimal CTL and HTL epitopes in vaccines has several potential advantages. Firstly, it is possible to use epitopes that are conserved thus targeting the majority of viral variants within a given clade or across clades. Secondly, epitopes from multiple viral structural or accessory gene products can be included in vaccines, which supports the induction cellular immune responses with significant breadth. Finally, dominance relationships between epitopes can be altered to increase immune recognition of subdominant epitopes. HTL and CTL epitopes from HIV-1 have recently been identified and characterized in numbers that are large enough to support their use in experimental vaccines. Initial studies with prototype DNA vaccines encoding epitopes indicate the need to include intracellular targeting sequences, to direct the encoded gene products to different cellular compartments, and amino acid spacer sequences between epitopes to optimize the processing, and subsequent presentation, of individual epitopes. Vaccines composed of CTL or HTL epitopes are now being developed for clinical testing.