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Hotspot Hunter: a computational system for large-scale screening and selection of candidate immunological hotspots in pathogen proteomes. G.L. Zhang, A.M. Khan , K.N. Srinivasan, A.T. Heiny, K.X. Lee, C.K. Kwoh, J.T. August and V. Brusic. Outline. Background & Motivations

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Hotspot hunter a computational system for large scale screening and selection of candidate immunological hotspots in pa 1348466

Hotspot Hunter: a computational system for large-scale screening and selection of candidate immunological hotspots in pathogen proteomes

G.L. Zhang, A.M. Khan, K.N. Srinivasan, A.T. Heiny, K.X. Lee,

C.K. Kwoh, J.T. August and V. Brusic


Hotspot hunter a computational system for large scale screening and selection of candidate immunological hotspots in pa 1348466

Outline screening and selection of candidate immunological hotspots in pathogen proteomes

Background & Motivations

System – Hotspot Hunter

Discussion


Identification of t cell epitopes for the study of vaccines and immunotherapies
Identification of T-cell epitopes for the study of vaccines and immunotherapies

Peptide

TCR

HLA

http://immuneweb.xxmc.edu.cn/Lymphoid%20System.files/UntiPCT8.jpeg


Hotspot hunter a computational system for large scale screening and selection of candidate immunological hotspots in pa 1348466

P1 and immunotherapies

Promiscuous epitopes

P2

P3

P4

One supertype

H1

H2

H3

H4

T-cell epitope clusters (hotspots) for the development of epitope-based vaccines

  • Promiscuous T-cell epitopes relevant to large proportion of the human population

  • Presence of clusters of promiscuous T-cell epitopes (hotspots) in antigens


Hotspot hunter a computational system for large scale screening and selection of candidate immunological hotspots in pa 1348466

Mapping hotspots experimentally is a challenging task and immunotherapies

  • Large size of pathogen proteomes (sequence length versus sequence number)

  • Low natural prevalence of T-cell epitopes (~1-5%) for a given HLA molecule

  • High cost of peptide synthesis

  • Limited access to human PBMC

  • Time-consumingexperimental assays

Peptide

TCR

HLA


Hotspot hunter a computational system for large scale screening and selection of candidate immunological hotspots in pa 1348466

Existing prediction systems are not suitable for large-scale study of hotspots in pathogen proteomes

  • Limitations of existing promiscuous epitope prediction systems

    • Single protein sequence per submission

    • Do not predict for hotspots

    • Impractical for large-scale systematic study of hotspots in large proteomes


Hotspot hunter a computational system for large scale screening and selection of candidate immunological hotspots in pa 1348466

Outline study of hotspots in pathogen proteomes

  • Background & Motivations

  • System – Hotspot Hunter

  • Discussion


Hotspot hunter a computational system for large scale screening and selection of candidate immunological hotspots in pa 1348466

http://antigen.i2r.a-star.edu.sg/hh/ study of hotspots in pathogen proteomes


Hotspot hunter a computational system for large scale screening and selection of candidate immunological hotspots in pa 1348466

Hotspot Hunter study of hotspots in pathogen proteomes

  • Screen and select of hotspots specific to four common HLA supertypes

    • HLA class I A2, A3, B7  cover ~ 88% of human population

    • HLA class II DR  cover ~100% of human population


Hotspot hunter a computational system for large scale screening and selection of candidate immunological hotspots in pa 1348466

Hotspot Hunter Implementation study of hotspots in pathogen proteomes

  • Predictive Engines  ANN and SVM methods

  • Predictions results integrated using soft computing principles

  • 10-fold cross-validation results showed that the system is of high accuracy


Hotspot hunter a computational system for large scale screening and selection of candidate immunological hotspots in pa 1348466

Hotspot Hunter can reliably identify real hotspots study of hotspots in pathogen proteomes

  • HLA-DR supertype specific hotspots for HCV Core protein sequence

Experimental verified

30-51

118-173

95-108

FP

30-47

FN

130-147

Hotspot Hunter predictions


Hotspot hunter a computational system for large scale screening and selection of candidate immunological hotspots in pa 1348466

Hotspot Hunter Functions study of hotspots in pathogen proteomes

  • Single sequence query

  • Multiple sequence query

  • Target selection

  • Selection of common hotspot across more than one HLA supertype


Hotspot hunter a computational system for large scale screening and selection of candidate immunological hotspots in pa 1348466

Khan et al. (2006) BMC Bioinformatics study of hotspots in pathogen proteomes


Hotspot hunter a computational system for large scale screening and selection of candidate immunological hotspots in pa 1348466

Outline study of hotspots in pathogen proteomes

Background & Motivations

System – Hotspot Hunter

Discussion


Hotspot hunter a computational system for large scale screening and selection of candidate immunological hotspots in pa 1348466

Hotspot Hunter is a new generation computational tool aiding in epitope-based vaccine design

  • Allows prediction of immunological hotspots

  • Combines the strengths of the ANN and SVM  robust prediction performance

  • Multiple sequence query  suitable for large-scale study

  • Provides a utility for selecting candidate hotspots and experimental targets


Hotspot hunter a computational system for large scale screening and selection of candidate immunological hotspots in pa 1348466

Application of Hotspot Hunter in epitope-based vaccine design

  • Our system can be customized and integrated into specialized databases

    • Tumor Antigen Database: http://research.i2r.a-star.edu.sg/Templar/DB/cancer_antigen/

    • CandiVF - Candida albicans Virulence Factor Database

Tongchusak et al., (2005) Int J Pep Res Ther.


Hotspot hunter a computational system for large scale screening and selection of candidate immunological hotspots in pa 1348466

Acknowledgment in epitope-based vaccine design

  • Funding Agency

    • NIH, USA


Hotspot hunter a computational system for large scale screening and selection of candidate immunological hotspots in pa 1348466

Validation using experimental binders in epitope-based vaccine design

  • Human pappilomavirus type 16 proteins E6 (Kast et al.,1994)

  • E6 hot-spot regions

  • HLA-A2 E6 7-34 (7-15, 18-26, and 26-34)

  • HLA-A2 E6 52-60 (single peptide)

  • HLA-A3 E6 33-67 (33-41, 42-50, and 59-67)

  • E6 75-101 (75-83, 89-97, and 93-101)

  • E6 125-151 (125-133 and 143-151)

E6

HLA-A2

HLA-A3