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HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

Dec 21, 2015

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Page 1: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.
Page 2: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

HLA

Page 3: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

HLA

MHCs are the gatekeepers of the immune system.

1.) LOCATE: Present peptides that may be viral.

2.) ACTIVATE: Activate immune defense mechanisms.

Page 4: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

HLAClass 1

8-10 AA 13-25 AA

Class 2

# ~80 # ~40 Closed Open

Page 5: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

HLA

Understanding the HLA:

Structural chemistry (x-ray crystallography), biological processes, role within the immune system, binding behavior, statistical distribution.2 ways of looking at this:

1.) Descriptive

2.) Functional

Page 6: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

HLA

Understanding the HLA:

Structural chemistry (x-ray crystallography), biological processes, role within the immune system, binding behavior, statistical distribution.2 ways of looking at this:

1.) Descriptive

2.) Functional

Page 7: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

What fits in an HLA?

Page 8: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

What fits in an HLA?

Find out experimentally?

# Class I HLA’s ≃ 80

Page 9: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

What fits in an HLA?

Find out experimentally?

# Class I HLA’s ≃ 80

# Possible 9-mers:

20^9 = 512,000,000,000 ≃ 10^11

Page 10: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

What fits in an HLA?

Calculate theoretically?

Binding Motifs

Quantitative Matrices

Molecular

Artificial Neural Network

Hidden Markov Models

Page 11: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

What fits in an HLA?

Binding Motifs:

Hypothesis: HLA binding entirely determined by a few AA (1-3) on the peptide.

Approach: Check peptide for anchor residue.

Calculate theoretically?

Page 12: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

What fits in an HLA?

Binding Motifs:

i.e A1 Serotype: X X [D/E] X X X [Y]

X X [D/E] X X X X [Y]

X X [D/E] X X X X X [Y]

Binds peptides: BK[D]LGGSD[Y]

AC[D]SWIH[Y]

Calculate theoretically?

Page 13: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

What fits in an HLA?

Quantitative Matrices:

Hypothesis: Binding is determined by AA on the specific HLA.

Approach: Construct a virtual matrix and determine a threshold value. Check if product of AA values in virtual matrix exceed threshold.

Calculate theoretically?

Page 14: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

What fits in an HLA?

Quantitative Matrices:

Calculate theoretically?

9-mer Coefficient Table for HLA_A3

Amino

Acid Type Position

1st 2n 3rd 4th 5th 6th 7th 8th 9th

A 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

C 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

D 0.300 0.100 1.000 1.000 1.000 1.000 1.000 1.000 0.100

E 0.300 0.300 1.000 1.500 1.000 1.000 1.000 1.000 0.100

F 1.000 0.100 5.000 1.000 3.000 3.000 3.000 1.000 10.000

G 3.000 0.100 1.000 1.500 1.000 1.000 0.300 1.000 0.100

. . .

V 1.000 10.000 1.500 1.000 1.500 3.000 1.000 1.000 1.000

W 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 1.000

Y 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 20.000

final

constant 0.002

Page 15: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

What fits in an HLA?

Quantitative Matrices:

Calculate theoretically?

9-mer Coefficient Table for HLA_A3

Amino

Acid Type Position

1st 2n 3rd 4th 5th 6th 7th 8th 9th

A 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

C 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

D 0.300 0.100 1.000 1.000 1.000 1.000 1.000 1.000 0.100

E 0.300 0.300 1.000 1.500 1.000 1.000 1.000 1.000 0.100

F 1.000 0.100 5.000 1.000 3.000 3.000 3.000 1.000 10.000

G 3.000 0.100 1.000 1.500 1.000 1.000 0.300 1.000 0.100

. . .

V 1.000 10.000 1.500 1.000 1.500 3.000 1.000 1.000 1.000

W 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 1.000

Y 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 20.000

final

constant 0.002

ADCGTVMCE

Page 16: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

What fits in an HLA?

Quantitative Matrices:

Calculate theoretically?

9-mer Coefficient Table for HLA_A3

Amino

Acid Type Position

1st 2n 3rd 4th 5th 6th 7th 8th 9th

A 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

C 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

D 0.300 0.100 1.000 1.000 1.000 1.000 1.000 1.000 0.100

E 0.300 0.300 1.000 1.500 1.000 1.000 1.000 1.000 0.100

F 1.000 0.100 5.000 1.000 3.000 3.000 3.000 1.000 10.000

G 3.000 0.100 1.000 1.500 1.000 1.000 0.300 1.000 0.100

. . .

V 1.000 10.000 1.500 1.000 1.500 3.000 1.000 1.000 1.000

W 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 1.000

Y 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 20.000

final

constant 0.002

ADCGTVMCE

Page 17: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

What fits in an HLA?

Quantitative Matrices:

Calculate theoretically?

9-mer Coefficient Table for HLA_A3

Amino

Acid Type Position

1st 2n 3rd 4th 5th 6th 7th 8th 9th

A 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

C 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

D 0.300 0.100 1.000 1.000 1.000 1.000 1.000 1.000 0.100

E 0.300 0.300 1.000 1.500 1.000 1.000 1.000 1.000 0.100

F 1.000 0.100 5.000 1.000 3.000 3.000 3.000 1.000 10.000

G 3.000 0.100 1.000 1.500 1.000 1.000 0.300 1.000 0.100

. . .

V 1.000 10.000 1.500 1.000 1.500 3.000 1.000 1.000 1.000

W 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 1.000

Y 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 20.000

final

constant 0.002

ADCGTVMCE

Page 18: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

What fits in an HLA?

Quantitative Matrices:

Calculate theoretically?

9-mer Coefficient Table for HLA_A3

Amino

Acid Type Position

1st 2n 3rd 4th 5th 6th 7th 8th 9th

A 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

C 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

D 0.300 0.100 1.000 1.000 1.000 1.000 1.000 1.000 0.100

E 0.300 0.300 1.000 1.500 1.000 1.000 1.000 1.000 0.100

F 1.000 0.100 5.000 1.000 3.000 3.000 3.000 1.000 10.000

G 3.000 0.100 1.000 1.500 1.000 1.000 0.300 1.000 0.100

. . .

V 1.000 10.000 1.500 1.000 1.500 3.000 1.000 1.000 1.000

W 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 1.000

Y 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 20.000

final

constant 0.002

ADCGTVMCE

Page 19: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

What fits in an HLA?

Quantitative Matrices:

Calculate theoretically?

9-mer Coefficient Table for HLA_A3

Amino

Acid Type Position

1st 2n 3rd 4th 5th 6th 7th 8th 9th

A 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

C 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

D 0.300 0.100 1.000 1.000 1.000 1.000 1.000 1.000 0.100

E 0.300 0.300 1.000 1.500 1.000 1.000 1.000 1.000 0.100

F 1.000 0.100 5.000 1.000 3.000 3.000 3.000 1.000 10.000

G 3.000 0.100 1.000 1.500 1.000 1.000 0.300 1.000 0.100

. . .

V 1.000 10.000 1.500 1.000 1.500 3.000 1.000 1.000 1.000

W 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 1.000

Y 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 20.000

final

constant 0.002

ADCGTVMCE

Page 20: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

What fits in an HLA?

Quantitative Matrices:

Calculate theoretically?

9-mer Coefficient Table for HLA_A3

Amino

Acid Type Position

1st 2n 3rd 4th 5th 6th 7th 8th 9th

A 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

C 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

D 0.300 0.100 1.000 1.000 1.000 1.000 1.000 1.000 0.100

E 0.300 0.300 1.000 1.500 1.000 1.000 1.000 1.000 0.100

F 1.000 0.100 5.000 1.000 3.000 3.000 3.000 1.000 10.000

G 3.000 0.100 1.000 1.500 1.000 1.000 0.300 1.000 0.100

. . .

V 1.000 10.000 1.500 1.000 1.500 3.000 1.000 1.000 1.000

W 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 1.000

Y 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 20.000

final

constant 0.002

ADCGTVMCE

Page 21: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

What fits in an HLA?

Quantitative Matrices:

Calculate theoretically?

9-mer Coefficient Table for HLA_A3

Amino

Acid Type Position

1st 2n 3rd 4th 5th 6th 7th 8th 9th

A 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

C 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

D 0.300 0.100 1.000 1.000 1.000 1.000 1.000 1.000 0.100

E 0.300 0.300 1.000 1.500 1.000 1.000 1.000 1.000 0.100

F 1.000 0.100 5.000 1.000 3.000 3.000 3.000 1.000 10.000

G 3.000 0.100 1.000 1.500 1.000 1.000 0.300 1.000 0.100

. . .

V 1.000 10.000 1.500 1.000 1.500 3.000 1.000 1.000 1.000

W 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 1.000

Y 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 20.000

final

constant 0.002

ADCGTVMCE

Page 22: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

What fits in an HLA?

Quantitative Matrices:

Calculate theoretically?

9-mer Coefficient Table for HLA_A3

Amino

Acid Type Position

1st 2n 3rd 4th 5th 6th 7th 8th 9th

A 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

C 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

D 0.300 0.100 1.000 1.000 1.000 1.000 1.000 1.000 0.100

E 0.300 0.300 1.000 1.500 1.000 1.000 1.000 1.000 0.100

F 1.000 0.100 5.000 1.000 3.000 3.000 3.000 1.000 10.000

G 3.000 0.100 1.000 1.500 1.000 1.000 0.300 1.000 0.100

. . .

V 1.000 10.000 1.500 1.000 1.500 3.000 1.000 1.000 1.000

W 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 1.000

Y 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 20.000

final

constant 0.002

ADCGTVMCE

Page 23: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

What fits in an HLA?

Quantitative Matrices:

Calculate theoretically?

9-mer Coefficient Table for HLA_A3

Amino

Acid Type Position

1st 2n 3rd 4th 5th 6th 7th 8th 9th

A 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

C 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

D 0.300 0.100 1.000 1.000 1.000 1.000 1.000 1.000 0.100

E 0.300 0.300 1.000 1.500 1.000 1.000 1.000 1.000 0.100

F 1.000 0.100 5.000 1.000 3.000 3.000 3.000 1.000 10.000

G 3.000 0.100 1.000 1.500 1.000 1.000 0.300 1.000 0.100

. . .

V 1.000 10.000 1.500 1.000 1.500 3.000 1.000 1.000 1.000

W 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 1.000

Y 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 20.000

final

constant 0.002

ADCGTVMCE

Page 24: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

What fits in an HLA?

Quantitative Matrices:

Calculate theoretically?

9-mer Coefficient Table for HLA_A3

Amino

Acid Type Position

1st 2n 3rd 4th 5th 6th 7th 8th 9th

A 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

C 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

D 0.300 0.100 1.000 1.000 1.000 1.000 1.000 1.000 0.100

E 0.300 0.300 1.000 1.500 1.000 1.000 1.000 1.000 0.100

F 1.000 0.100 5.000 1.000 3.000 3.000 3.000 1.000 10.000

G 3.000 0.100 1.000 1.500 1.000 1.000 0.300 1.000 0.100

. . .

V 1.000 10.000 1.500 1.000 1.500 3.000 1.000 1.000 1.000

W 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 1.000

Y 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 20.000

final

constant 0.002

ADCGTVMCE

Page 25: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

What fits in an HLA?

Quantitative Matrices:

Calculate theoretically?

9-mer Coefficient Table for HLA_A3

Amino

Acid Type Position

1st 2n 3rd 4th 5th 6th 7th 8th 9th

A 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

C 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

D 0.300 0.100 1.000 1.000 1.000 1.000 1.000 1.000 0.100

E 0.300 0.300 1.000 1.500 1.000 1.000 1.000 1.000 0.100

F 1.000 0.100 5.000 1.000 3.000 3.000 3.000 1.000 10.000

G 3.000 0.100 1.000 1.500 1.000 1.000 0.300 1.000 0.100

. . .

V 1.000 10.000 1.500 1.000 1.500 3.000 1.000 1.000 1.000

W 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 1.000

Y 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 20.000

final

constant 0.002

ADCGTVMCE

Page 26: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

What fits in an HLA?

Quantitative Matrices:

Calculate theoretically?

9-mer Coefficient Table for HLA_A3

Amino

Acid Type Position

1st 2n 3rd 4th 5th 6th 7th 8th 9th

A 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

C 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

D 0.300 0.100 1.000 1.000 1.000 1.000 1.000 1.000 0.100

E 0.300 0.300 1.000 1.500 1.000 1.000 1.000 1.000 0.100

F 1.000 0.100 5.000 1.000 3.000 3.000 3.000 1.000 10.000

G 3.000 0.100 1.000 1.500 1.000 1.000 0.300 1.000 0.100

. . .

V 1.000 10.000 1.500 1.000 1.500 3.000 1.000 1.000 1.000

W 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 1.000

Y 1.000 0.100 5.000 1.000 3.000 1.000 3.000 1.000 20.000

final

constant 0.002

ADCGTVMCE

1.0 x 0.1 x 1.0 x 1.5 x 3.0 x 3.0 x 3.0 x 1.0 x 10.0 x 0.002

= 0.081

Page 27: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

What fits in an HLA?

Quantitative Matrices:

Calculate theoretically?

If 0.081 > threshold, then ADCGTVMCE is bound by class I HLA A3.

Page 28: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

Vaccination

Page 29: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

Vaccination

1.) Determine a ‘good’ viral peptide sequence.

2.) Create and inject these peptides.

- Candidate peptide bound and presented on HLA- Stimulate immune response

- Subject is protected from virus

Page 30: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

Vaccination

What is a ‘good’ viral peptide sequence?

0.) Fits HLA

1.) Minimal overlap with self-peptides

2.) Preserved through genetic mutations

3.) Binds strongly to HLA

Page 31: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

Vaccination

What is a ‘good’ viral peptide sequence?

0.) Fits HLA

1.) Minimal overlap with self-peptides

2.) Preserved through genetic mutations

3.) Binds strongly to HLA

Ideally: Fits all HLA (of type I or II)

Page 32: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

Vaccination

What is a ‘good’ viral peptide sequence?

0.) Fits HLA

1.) Minimal overlap with self-peptides

2.) Preserved through genetic mutations

3.) Binds strongly to HLA

Ideally: No overlap with self-peptides

Page 33: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

Vaccination

What is a ‘good’ viral peptide sequence?

0.) Fits HLA

1.) Minimal overlap with self-peptides

2.) Preserved through genetic mutations

3.) Binds strongly to HLA

Ideally: Sequence is perfectly conserved

Page 34: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

Vaccination

What is a ‘good’ viral peptide sequence?

0.) Fits HLA

1.) Minimal overlap with self-peptides

2.) Preserved through genetic mutations

3.) Binds strongly to HLA

Ideally: Binds optimally to HLA

Page 35: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

HIV1-B

Page 36: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

HIV1-B

Total AA length of proteins ≃ 3000 AA

Page 37: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

HIV1-B

Peptides considered from protein segments.

Considered within class 1 HLAs only.

Quantitative matrix of 9-mers.Parker, K. C., M. A. Bednarek, and J. E. Coligan. 1994. Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. J. Immunol. 152:163

Page 38: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

1. SelfOf peptides bound by HLAs, which viral 9-mer peptides are not in self?

Self 9-mers bound by HLAsAAAAAAAI AAAAAAAAL AAAAAAAAV AAAAAAAGV

AAAAAAAHL AAAAAAAKM AAAAAAALV AAAAAAANI

AAAAAAANL AAAAAAAPV AAAAAAASL AAAAAAAVI

AAAAAAAVV AAAAAADKL AAAAAADKW AAAAAAFKL

AAAAAAGEL AAAAAAGGL AAAAAAGGV AAAAAAGKL

AAAAAAGQI AAAAAAGRV AAAAAAGSL AAAAAAIGI

AAAAAALAL AAAAAALCV AAAAAALDL AAAAAALTL

. . .

Page 39: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

1. SelfOf peptides bound by HLAs, which viral 9-mer peptides are not in self?

Viral 9-mers bound by HLAsAACWWAGIK AACWWAGIK ADDTVLEEM AELELAENR

AETFYVDGA AETFYVDGA AETFYVDGA AETFYVDGA

AETGQETAY AETGQETAY AEVIPAETG AEVIPAETG

AFSPEVIPM AGDDCVASR AGERIVDII AGERIVDII

AGERIVDII AGERIVDII AGERIVDII AGIKQEFGI

AGIKQEFGI AGIKQEFGI AGIKQEFGI AGIRKVLFL

AGIRKVLFL AGIRKVLFL AGIRKVLFL AGIRKVLFL

. . .

Page 40: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

1. SelfOf peptides bound by HLAs, which viral 9-mer peptides are not in self?

None!

No viral 9-mer peptides are in self.

Page 41: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

1. SelfOf peptides bound by HLAs, which viral 9-mer peptides are not in self?

# Possible 9-mers:

20^9 = 512,000,000,000 ≃ 10^11# Human 9-mers:

= 2,981,644 = 10^6# Human / # Possible 9-mers = 10^-5No autoimmune symptoms.

Page 42: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

2. ConservedWhich viral peptides sequences are preserved through genetic mutations?

Page 43: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

2. ConservedWhich viral peptides sequences are preserved through genetic mutations? Alignment Program: ClustalX

v1.8

Selection of env Proteins, AA: 1 - 70

Page 44: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

2. ConservedWhich viral peptides sequences are preserved through genetic mutations? Alignment Program: ClustalX

v1.8

Selection of env Proteins, AA: 100 - 160

Page 45: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

2. ConservedWhich viral peptides sequences are preserved through genetic mutations? Alignment Program: ClustalX

v1.8

Selection of env Proteins, AA: 170 - 240

Page 46: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

2. ConservedWhich viral peptides sequences are preserved through genetic mutations? Alignment Program: ClustalX

v1.8

Selection of env Proteins, AA: 800 -

Page 47: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

2. ConservedWhich viral peptides sequences are preserved through genetic mutations?

Align protein sequences: Match conserved segments to each other

Virus 1: [A] [B] [C] [Y] [A] [B] [C] …

Virus 1’: [A] [B] [C] [A] [Y] [A] [B] [C] …

Page 48: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

2. ConservedWhich viral peptides sequences are preserved through genetic mutations?

Align protein sequences: Match conserved segments to each other

Virus 1: [A] [B] [C] --- [Y] [A] [B] [C] …

Virus 1’: [A] [B] [C] [A] [Y] [A] [B] [C] …

Page 49: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

2. ConservedWhich viral peptides sequences are preserved through genetic mutations? Alignment Program: ClustalX

v1.8

Selection of env Proteins, AA: 1 - 70

Page 50: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

2. ConservedWhich viral peptides sequences are preserved through genetic mutations? Alignment Program: ClustalX

v1.8

Selection of env Proteins, AA: 100 - 160

Page 51: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

2. ConservedWhich viral peptides sequences are preserved through genetic mutations? Alignment Program: ClustalX

v1.8

Selection of env Proteins, AA: 170 - 240

Page 52: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

2. ConservedWhich viral peptides sequences are preserved through genetic mutations? Alignment Program: ClustalX

v1.8

Selection of env Proteins, AA: 800 -

Page 53: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

2. ConservedWhich viral peptides sequences are preserved through genetic mutations?

Considering only those that are completely conservedTotal # sequences = 537

Page 54: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

2. ConservedWhich viral peptides sequences are preserved through genetic mutations?

Considering only those that are completely conservedTotal # sequences > 8 AA = 76

1 : 177 2 : 93 3 : 71 4 : 50 5 : 28 6 : 18 7 : 14 8 : 10 9 : 6 10 : 3 11 : 9

12 : 3 13 : 3 14 : 3 15 : 5 16 : 3 17 : 1 18 : 2 19 : 2 20 : 3 22 : 1 23 : 2

24 : 1 25 : 4 26 : 3 29 : 1 30 : 4 34 : 1 37 : 1 38 : 1 40 : 1 41 : 1 43 : 1

47 : 1 48 : 2 49 : 1 51 : 1 52 : 1 57 : 1 59 : 1 60 : 1 72 : 1 87 : 1

Page 55: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

2. ConservedWhich viral peptides sequences are preserved through genetic mutations?

Which of these conserved sequences make ‘good’ candidate peptides?

DDTVLEEHKAIGTTHLEG - conserved 19 AA sequenceDDTVLEEHKAIGTTHLEGDDTVLEEHKAIGTTHLEG

DDTVLEEHKAIGTTHLEG

DDTVLEEHKAIGTTHLEGDDTVLEEHKAIGTTHLEG

DDTVLEEHKAIGTTHLEGDDTVLEEHKAIGTTHLEGDDTVLEEHKAIGTTHLEGDDTVLEEHKAIGTTHLEG

peptides to be tested

DDTVLEEHKAIGTTHLEG

Page 56: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

0. Fitting the HLA

Page 57: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

0. Fitting the HLACan we fit all HLAs?

Page 58: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

0. Fitting the HLACan we fit all HLAs?For certain proteins:

env, pol (1,2), gag, tat

Page 59: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

0. Fitting the HLA # f S HLA

1 1 CSGKLICTT 4

2 2 CVKLTPLCV 10 1

3 1 DNWRSELYK 19

4 3 FLGAAGSTM 7 19 33

5 3 GAAGSTMGA 6 2 27

6 1 GCSGKLICT 10

7 1 GFLGAAGST 13

8 10 GIVQQQNNL 33 2 3 11 13 18 19 26 30 32

9 7 IVQQQNNLL 33 1 11 13 18 22 32

10 10 KLTPLCVTL 7 3 11 12 13 18 19 24 32 33

11 1 LGFLGAAGS 2

12 9 LTVWGIKQL 9 2 3 11 13 18 26 30 32

13 1 NVSTVQCTH 1

14 1 NWRSELYKY 13

15 2 RSELYKYKV 4 20

16 1 SGIVQQQNN 2

17 3 STVQCTHGI 3 2 27

18 1 VKLTPLCVT 26

19 1 WGCSGKLIC 5

20 1 WGIKQLQAR 16

21 2 WRSELYKYK 24

Page 60: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

0. Fitting the HLACan we fit all HLAs?For certain proteins:

Optimal set of candidate sequences for a given protein?

env, pol (1,2), gag, tat

Page 61: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

0. Fitting the HLACan we fit all HLAs?For certain proteins:

Optimal set of candidate sequences for a given protein?

Classical network algorithm : Min-cost-Max-flow

env, pol (1,2), gag, tat

Page 62: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

0. Fitting the HLA # f S HLA Least :

1 1 CSGKLICTT 4 15 10 8 5 4 2

2 2 CVKLTPLCV 10 1

3 1 DNWRSELYK 19

4 3 FLGAAGSTM 7 19 33

5 3 GAAGSTMGA 6 2 27

6 1 GCSGKLICT 10

7 1 GFLGAAGST 13

8 10 GIVQQQNNL 33 2 3 11 13 18 19 26 30 32

9 7 IVQQQNNLL 33 1 11 13 18 22 32

10 10 KLTPLCVTL 7 3 11 12 13 18 19 24 32 33

11 1 LGFLGAAGS 2

12 9 LTVWGIKQL 9 2 3 11 13 18 26 30 32

13 1 NVSTVQCTH 1

14 1 NWRSELYKY 13

15 2 RSELYKYKV 4 20

16 1 SGIVQQQNN 2

17 3 STVQCTHGI 3 2 27

18 1 VKLTPLCVT 26

19 1 WGCSGKLIC 5

20 1 WGIKQLQAR 16

21 2 WRSELYKYK 24

Page 63: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

0. Fitting the HLA # f S HLA Least :

1 1 CSGKLICTT 4 15 10 8 5 4 2

2 2 CVKLTPLCV 10 1

3 1 DNWRSELYK 19

4 3 FLGAAGSTM 7 19 33

5 3 GAAGSTMGA 6 2 27

6 1 GCSGKLICT 10

7 1 GFLGAAGST 13

8 10 GIVQQQNNL 33 2 3 11 13 18 19 26 30 32

9 7 IVQQQNNLL 33 1 11 13 18 22 32

10 10 KLTPLCVTL 7 3 11 12 13 18 19 24 32 33

11 1 LGFLGAAGS 2

12 9 LTVWGIKQL 9 2 3 11 13 18 26 30 32

13 1 NVSTVQCTH 1

14 1 NWRSELYKY 13

15 2 RSELYKYKV 4 20

16 1 SGIVQQQNN 2

17 3 STVQCTHGI 3 2 27

18 1 VKLTPLCVT 26

19 1 WGCSGKLIC 5

20 1 WGIKQLQAR 16

21 2 WRSELYKYK 24

Page 64: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

0. Fitting the HLA # f S HLA Least :

1 1 CSGKLICTT 4 15 10 8 5 4 2

2 2 CVKLTPLCV 10 1

3 1 DNWRSELYK 19

4 3 FLGAAGSTM 7 19 33

5 3 GAAGSTMGA 6 2 27

6 1 GCSGKLICT 10

7 1 GFLGAAGST 13

8 10 GIVQQQNNL 33 2 3 11 13 18 19 26 30 32

9 7 IVQQQNNLL 33 1 11 13 18 22 32

10 10 KLTPLCVTL 7 3 11 12 13 18 19 24 32 33

11 1 LGFLGAAGS 2

12 9 LTVWGIKQL 9 2 3 11 13 18 26 30 32

13 1 NVSTVQCTH 1

14 1 NWRSELYKY 13

15 2 RSELYKYKV 4 20

16 1 SGIVQQQNN 2

17 3 STVQCTHGI 3 2 27

18 1 VKLTPLCVT 26

19 1 WGCSGKLIC 5

20 1 WGIKQLQAR 16

21 2 WRSELYKYK 24

Page 65: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

0. Fitting the HLA # f S HLA Least :

1 1 CSGKLICTT 4 15 10 8 5 4 2

2 2 CVKLTPLCV 10 1

3 1 DNWRSELYK 19

4 3 FLGAAGSTM 7 19 33

5 3 GAAGSTMGA 6 2 27

6 1 GCSGKLICT 10

7 1 GFLGAAGST 13

8 10 GIVQQQNNL 33 2 3 11 13 18 19 26 30 32

9 7 IVQQQNNLL 33 1 11 13 18 22 32

10 10 KLTPLCVTL 7 3 11 12 13 18 19 24 32 33

11 1 LGFLGAAGS 2

12 9 LTVWGIKQL 9 2 3 11 13 18 26 30 32

13 1 NVSTVQCTH 1

14 1 NWRSELYKY 13

15 2 RSELYKYKV 4 20

16 1 SGIVQQQNN 2

17 3 STVQCTHGI 3 2 27

18 1 VKLTPLCVT 26

19 1 WGCSGKLIC 5

20 1 WGIKQLQAR 16

21 2 WRSELYKYK 24

Page 66: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

0. Fitting the HLA # f S HLA Least :

1 1 CSGKLICTT 4 15 10 8 5 4 2

2 2 CVKLTPLCV 10 1

3 1 DNWRSELYK 19

4 3 FLGAAGSTM 7 19 33

5 3 GAAGSTMGA 6 2 27

6 1 GCSGKLICT 10

7 1 GFLGAAGST 13

8 10 GIVQQQNNL 33 2 3 11 13 18 19 26 30 32

9 7 IVQQQNNLL 33 1 11 13 18 22 32

10 10 KLTPLCVTL 7 3 11 12 13 18 19 24 32 33

11 1 LGFLGAAGS 2

12 9 LTVWGIKQL 9 2 3 11 13 18 26 30 32

13 1 NVSTVQCTH 1

14 1 NWRSELYKY 13

15 2 RSELYKYKV 4 20

16 1 SGIVQQQNN 2

17 3 STVQCTHGI 3 2 27

18 1 VKLTPLCVT 26

19 1 WGCSGKLIC 5

20 1 WGIKQLQAR 16

21 2 WRSELYKYK 24

Page 67: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

0. Fitting the HLA # f S HLA Least :

1 1 CSGKLICTT 4 15 10 8 5 4 2

2 2 CVKLTPLCV 10 1

3 1 DNWRSELYK 19

4 3 FLGAAGSTM 7 19 33

5 3 GAAGSTMGA 6 2 27

6 1 GCSGKLICT 10

7 1 GFLGAAGST 13

8 10 GIVQQQNNL 33 2 3 11 13 18 19 26 30 32

9 7 IVQQQNNLL 33 1 11 13 18 22 32

10 10 KLTPLCVTL 7 3 11 12 13 18 19 24 32 33

11 1 LGFLGAAGS 2

12 9 LTVWGIKQL 9 2 3 11 13 18 26 30 32

13 1 NVSTVQCTH 1

14 1 NWRSELYKY 13

15 2 RSELYKYKV 4 20

16 1 SGIVQQQNN 2

17 3 STVQCTHGI 3 2 27

18 1 VKLTPLCVT 26

19 1 WGCSGKLIC 5

20 1 WGIKQLQAR 16

21 2 WRSELYKYK 24

Page 68: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

0. Fitting the HLA # f S HLA Least :

1 1 CSGKLICTT 4 15 10 8 5 4 2

2 2 CVKLTPLCV 10 1

3 1 DNWRSELYK 19

4 3 FLGAAGSTM 7 19 33

5 3 GAAGSTMGA 6 2 27

6 1 GCSGKLICT 10

7 1 GFLGAAGST 13

8 10 GIVQQQNNL 33 2 3 11 13 18 19 26 30 32

9 7 IVQQQNNLL 33 1 11 13 18 22 32

10 10 KLTPLCVTL 7 3 11 12 13 18 19 24 32 33

11 1 LGFLGAAGS 2

12 9 LTVWGIKQL 9 2 3 11 13 18 26 30 32

13 1 NVSTVQCTH 1

14 1 NWRSELYKY 13

15 2 RSELYKYKV 4 20

16 1 SGIVQQQNN 2

17 3 STVQCTHGI 3 2 27

18 1 VKLTPLCVT 26

19 1 WGCSGKLIC 5

20 1 WGIKQLQAR 16

21 2 WRSELYKYK 24

Page 69: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

Candidate sequences

CVKLTPLCV // FLGAAGSTM // GAAGSTMGA // GIVQQQNNL // KLTPLCVTL // RSELYKYKV

HIV1-B env Protein (all)

HIV1-B tat Protein (1,2,15,16,17,19,27)EPWKHPGSQ // GISYGRKKR

HIV1-B pol(1) Protein (all) 14

HIV1-B pol(2) Protein (all) 11

HIV1-B gag Protein (all but 15, 19, 21) 9

Page 70: HLA MHCs are the gatekeepers of the immune system. 1.) LOCATE: Present peptides that may be viral. 2.) ACTIVATE: Activate immune defense mechanisms.

Implementation

“Sequence signals for generation of antigenic peptides by the proteasome: implications for proteasomal cleavage mechanism.”Altuvia Y, Margalit H

CVKLTPLCV // FLGAAGSTM // GAAGSTMGA // GIVQQQNNL // KLTPLCVTL // RSELYKYKV

// = Cleave signal.


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