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

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 (HR1) T-20 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 NH2 C-C HR2 FP HR1 T-20 TM // COOH � 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 M. Obermeier 4/2007

mutations HR-1 NH2 C-C HR2 FP HR1 TM // COOH G36 N43 � � � D: -450x � D: -249x � E: -43x � K/S: -6x � S: -29x L45 � V38 � M: 1,4x � � A: -60x � E: 1.100x V38A + N42D: -140x � Q40 V38A + N42T: -149x � � � H: -19x V38E + N42S: -513x � N42 N42T + N43K: -252x � � � D: >10x N42T + N43S: -339x � � T: 4x Q40H + L45M: -327x � Mink M. et al. (J. Virol. 2005), Wei X. et al. (AAC 2002) 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 M. Obermeier 4/2007

mutations HR-2 NH2 C-C HR2 FP HR1 TM // COOH � 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 Baldwin CE. et al (J. Virol. 2004), Xu L. et al. (AAC 2005) M. Obermeier 4/2007

Observations at the MvP NH2 C-C HR2 FP HR1 TM // COOH � 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 � 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 M. Obermeier 4/2007

Interaction of mutations HR1 and HR2 - intramolecular WT MUT MUT MUT L45 45M 45Q N42 138A 138A 138A V38 38A S138 M. Obermeier 4/2007

Interaction of mutations HR1 and HR2 - intermolecular N126 126K N43 43D M. Obermeier 4/2007

M. Obermeier 4/2007 gp41 Ausgabe

� 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