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

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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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slide1

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

slide2

Outline

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

slide4

P1

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
slide5

Mapping hotspots experimentally is a challenging task

  • 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

slide6

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
slide7

Outline

  • Background & Motivations
  • System – Hotspot Hunter
  • Discussion
slide9

Hotspot Hunter

  • 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
slide10

Hotspot Hunter Implementation

  • 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
slide11

Hotspot Hunter can reliably identify real hotspots

  • 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

slide12

Hotspot Hunter Functions

  • Single sequence query
  • Multiple sequence query
  • Target selection
  • Selection of common hotspot across more than one HLA supertype
slide17

Outline

Background & Motivations

System – Hotspot Hunter

Discussion

slide18

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
slide19

Application of Hotspot Hunter

  • 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.

slide20

Acknowledgment

  • Funding Agency
    • NIH, USA
slide21

Validation using experimental binders

  • 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

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