Analysis of T-20 resistance HIV-genome - - PDF document

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Analysis of T-20 resistance HIV-genome - - PDF document

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M. Obermeier 4/2007 Analysis of T-20 resistance HIV-genome http://www.hiv.lanl.gov/content/hiv-db/MAP/landmark.html M. Obermeier 4/2007 M. Obermeier 4/2007 Struktur gp41 T-20 loop C-terminal heptad repeat (HR2) N-terminal heptad repeat

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SLIDE 1
  • M. Obermeier 4/2007

Analysis of T-20 resistance

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SLIDE 2
  • M. Obermeier 4/2007

HIV-genome

http://www.hiv.lanl.gov/content/hiv-db/MAP/landmark.html

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SLIDE 3
  • M. Obermeier 4/2007

Struktur gp41

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SLIDE 4
  • M. Obermeier 4/2007

T-20

N-terminal heptad repeat (HR1) C-terminal heptad repeat (HR2)

T-20

loop

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SLIDE 5
  • M. Obermeier 4/2007

Why are we interested in resistance against T-20

T-20 is expansive T-20 is not easy for the patient We could learn, ... what amount of replication inhibition can be

assigned to effects of T-20

to predict T-20 response if T-20 can be used again after discontinuation

NH2 C-C TM COOH

//

HR2 FP HR1 T-20

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SLIDE 6
  • M. Obermeier 4/2007

mutations HR-1

  • G36

D: -450x E: -43x S: -29x

  • V38

A: -60x E: 1.100x

  • Q40

H: -19x

  • N42

D: >10x T: 4x

  • N43

D: -249x K/S: -6x

  • L45

M: 1,4x

  • V38A + N42D: -140x
  • V38A + N42T: -149x
  • V38E + N42S: -513x
  • N42T + N43K: -252x
  • N42T + N43S: -339x
  • Q40H + L45M: -327x

NH2 C-C TM COOH

//

HR2 FP HR1

Mink M. et al. (J. Virol. 2005), Wei X. et al. (AAC 2002)

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SLIDE 7
  • M. Obermeier 4/2007

Duration of T-20 therapy and proportion of resistant populations after T-20 discontinuation

  • C. Charpentier et al., Kinetics of Disappearance of Enfuvirtide-Resistance HIV-1 Mutations

After Drug Discontinuation…, 14 th CROI, Los Angeles, 2007; Poster M-134

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SLIDE 8
  • M. Obermeier 4/2007

mutations HR-2

G38A + N126K: T-20 dependant N43D + S138A:

47x

N43D + S138:

15x

N43 + S138A:

3x Observed combinations

S138A + G36V/D V38A + combinations with N42Q, N43Q/T

NH2 C-C TM COOH

//

HR2 FP HR1

Baldwin CE. et al (J. Virol. 2004), Xu L. et al. (AAC 2005)

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SLIDE 9
  • M. Obermeier 4/2007

Observations at the MvP

80 samples of 24 T-20 treated patients

1-15 samples per patient

23 patients acquired mutations

(atypical aa on highly conseved positions)

18 Pat. with mutations in HR1 15 Pat. with additional mutations in HR2 13 Pat. with additional mutations between HR1 and HR2

  • 0 Pat. with mutations only in HR2
  • 2 Pat. with mutations only in HR1 und HR2
  • 1 Pat. with mutations only in HR1

NH2 C-C TM COOH

//

HR2 FP HR1

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SLIDE 10
  • M. Obermeier 4/2007

Mutations in HR-2 as compensatory effect?

patient 6: 23-04-2002: no mutations 21-05-2002: start T-20 16-07-2002: N43D 10-12-2002: N43D +S138A

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SLIDE 11
  • M. Obermeier 4/2007

Interaction of mutations HR1 and HR2 - intramolecular

S138 138A 138A 138A V38 38A L45 45M 45Q N42

WT MUT MUT MUT

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SLIDE 12
  • M. Obermeier 4/2007

Interaction of mutations HR1 and HR2 - intermolecular

N126 126K N43 43D

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SLIDE 13
  • M. Obermeier 4/2007

gp41 Ausgabe

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SLIDE 14

HIV-GRADE e.V Thomas Berg, Medizinisches Labor Dr. Berg, Berlin Patrick Braun, PZB, Aachen Martin Däumer, Institut für Virologie, Köln Josef Eberle, Pettenkofer-Institut, München Robert Ehret, PZB Aachen Rolf Kaiser, Institut für Virologie, Köln Nils Kleinkauf, Charité, Berlin Klaus Korn, NRZ für Retroviren, Erlangen Harm Müller, Fenner-Labor, Hamburg Martin Stürmer, Institut für Medizinische Virologie, Frankfurt Hauke Walter, NRZ für Retroviren, Erlangen MvP: G. Thole

  • Prof. Bogner
  • Dr. Jäger