Etravirine Resistance Mutations and Immune selection Sandra Mller - - PowerPoint PPT Presentation

▶
etravirine resistance mutations and immune selection
SMART_READER_LITE
LIVE PREVIEW

Etravirine Resistance Mutations and Immune selection Sandra Mller - - PowerPoint PPT Presentation

Aug 24, 2022 381 likes •549 views

Etravirine Resistance Mutations and Immune selection Sandra Mller Department for Internal Medicine 3 and Institute for Clinical Immunology University of Erlangen-Nuremberg Background information about Peptide presentation

slide-1
SLIDE 1

Etravirine Resistance Mutations and Immune selection

Sandra Müller

Department for Internal Medicine 3 and Institute for Clinical Immunology University of Erlangen-Nuremberg

slide-2
SLIDE 2

2

Background information

… about

  • Peptide presentation
  • Epitopes
  • HLA and disease progression
  • Escape mutation

was given by Finja

in contrast to Finja’s project we analyse correlation between HLA alleles and the occurrence of drug resistance mutations in patients without primary resistance

e.g. Mueller et al. 2007 JVi

slide-3
SLIDE 3

3

Etravirine Resistance

  • non-nucleoside reverse transcriptase inhibitor (NNRTI)
  • high genetic barrier to the development of resistance
  • active against HIV-1 strains with multiple NNRTI

resistance mutations

  • resistance is evaluated by a score system
slide-4
SLIDE 4

4

Etravirine Tibotech Resistance Score

slide-5
SLIDE 5

5

Mojgan Haddad, Croi 2010 Poster 574

Etravirine Resistance Score - revised

Monogram score: New algorithm for detecting resistance to ETR based on correlation between genotypic data and phenotypic response in Monogram Assay More Mutations play a role new aa residues were included

  • ther exchanges

for some exchanges score changed

slide-6
SLIDE 6

6

Aim of Study – Interaction CTL and ETR Resistance?

Analyze influence of immune selection on ETR drug resistance mutations

  • Cohort of 237 chronically infected HIV-1 patients
  • 107 patients with out therapy before resistance testing
  • 87 patients were NNRTI experienced
  • 43 patients who were on therapy prior to resistance

testing but had no NNRTI

slide-7
SLIDE 7

7

Methods

serological or/and genotypic HLA-typing was performed – HLA A, HLA B and HLA Cw were determined

HIV-1 RT sequences were determined (Resistance testing)

univariate correlations were evaluated by Fisher’s exact test Next step:

results will be verified in biological assays: γ-interferon ELISPOT analyses restriction analyses standard Cr51 release assays

slide-8
SLIDE 8

8

Results – correlations between ETR resistance mutation and HLA alleles

all patients drug naive patients NNRTI experienced patients Resina patients Patients on NNRTI free therapies A98G V90I K103R V106I V179D V179E E138A Y181C V179T G190S M230L Y181I Cw2 Cw4 Cw5 Cw3 V189I Cw7 K101Q V90I K103R V106I V179D V179I E138A Y181C V179 G190A M230L Y181 A3 A23 A11 V189I A24 A26 A31 A33 A68 A25 A36 A98G V90I K103R V106I V179D V179I E138A Y181C V179T Y188L M230L Y181I B13 B35 B07 B57 B58 B62 B18 V189I B65 B44

slide-9
SLIDE 9

9

Results – Described Epitopes

reference sequence: YTAFTIPSINNETPGIRYQYNVLP described epitope: NETPGIRYQY Correlation between E138A and HLA-B*18 P=0.017 Odds ratio=26.118 TBTC score 1 .5 Mono score 3

slide-10
SLIDE 10

10

Results – Potential Epitopes

V90I

reference sequence: RELNKRTQDFWEVQLGIPHPAGLK potential epitopes: EVQLGIPHP HLA-A*68: syfpeithi ELNKRTQDFwev HLA-A*26: NetChop proteasome cleavage TQDFWEVQL HLA-B*13

K103R

reference sequence: VQLGIPHPAGLKKKKSVTVLDVGDA potential epitopes: HPAGLKKKK HLA-B*35: ELF PAGLKKKKS HLA-B*35: ELF KKKKSVTVL HLA-Cw*0301: ELF KKKKSVTVL HLA-Cw*0702: ELF

V106I

reference sequence: HPAGLKKKKSVTVLDVGDAYF potential epitopes: SVTVLDVGD HLA-A*11: syfpeithi HPAGLKKKKsv HLA-A*11: NetChop proteasome cleavage

V179I/D

reference sequence: LEPFRKQNPDIVIYQYMDDLCVGS potential epitopes: IVIYQYMDDL HLA-B*6802 RKQNPDIV HLA-B*65: syfpeithi RKQNPDIVI HLA-Cw*0301: ELF PDIVIYQYM HLA-Cw*0301: ELF

slide-11
SLIDE 11

11

Results – Recognition of VIYQYMDDL

Recognition in HLA-A*02+ patients VL9 includes aa position 179 V179E leads to escape Monogram score: 3

E-------- T-------- I-------- VIYQYMDDL

Chromium Release Assay

10 20 30 40 50 60 70 80 % Specific Lysis

A*02 and A*68 belong to the same HLA supertype

A*0201 x[LM]xxxxxx[VL] A*0205 x[V(QL)]xxxxxx[L] A*6802 x[TV]xxxxxx[VL]

slide-12
SLIDE 12

12

Conclusion

ETR m utations could be assigned to specific HLA alleles

Potential epitopes w ere found in the respective regions of HI V-1 RT

E1 3 8 A correlates to HLA B* 1 8 , lies in a HLA B* 1 8 epitope and m ost likely lead to im m une escape

I n HLA A* 0 2 + patients V1 7 9 E is an escape m utation Please send us blood sam ples from patients show ing Etravirine resistance m utations.

slide-13
SLIDE 13

13

Thom as Harrer

Kathrin Eism ann Silke Bergm ann Melanie Leykauf Ellen Harrer Hauke W alter Bernd Spriew ald Thom as‘ Group in Erlangen

Thanks to…

All Patients taking part in our studies Rolf Kaiser

Finja Schw eizer and colleagues RESI NA

DFG,I ZKF, Hector Stiftung HI V Kom petenznetz

slide-14
SLIDE 14

14

Fortsetzung Epitope

V179

reference sequence: LEPFRKQNPDIVIYQYMDDLCVGS potential epitopes: VIYQYMDDL HLA-B*6802 RKQNPDIVI HLA-Cw*0301: ELF NPDIVIYQY HLA-Cw*0401: ELF PDIVIYQYM HLA-Cw*0301: ELF VIYQYMDDL HLA-Cw*0301: ELF

Y181

reference sequence: PFRKQNPDIVIYQYMDDLCVGSDL potential epitopes: FRKQNPDIViy HLA B*3901 ELF; syfpeithi, potential CS KQNPDIVIY HLA A*03: syfpeithi RKQNPDIVI HLA B*3902 syfpeithi, potential CS

V189I reference sequence:

IVIYQYMDDLCVGSDLEIGQHRTK potential epitopes: vgSDLEIGQHR HLA A33 ELF; potential CS

slide-15
SLIDE 15

15

Fortsetzung Epitope

G190S M230Lreference sequence:

KHQKEPPFLWMGYELHPDKWTVQ potential epitopes: PFLWMGYEL NetChop WB GYELHPDKW evtl W als cleavage site reference sequence: IVIYQYMDDLCVGSDLEIGQHRTK potential epitopes: vgSDLEIGQHR HLA A33 ELF; potential CS YQYMDDLCV HLA B*3902 syfpeithi