Paul-Ehrlich-Institut Bundesamt für Sera und Impfstoffe Analysis of HIV evolution in a stem cell transplanted HIV patient: indications for in silico modelling AREVIR-GenaFor-Meeting 24.04.2009 Paul-Ehrlich-Institut Barbara Schnierle - Christel Kamp 1/12
Paul-Ehrlich-Institut Bundesamt für Sera und Impfstoffe Our data basis A case study: HIV and stem cell transplantation Coreceptor usage: Phenotype testing vs. in silico prediction Paul-Ehrlich-Institut Barbara Schnierle - Christel Kamp 2/12
Paul-Ehrlich-Institut Our data basis Bundesamt für Sera und Impfstoffe Comprehensive longitudinal patient data Numbers Comments Patients (total) 291 co-information on viral load, CD4 counts, therapy, co-infections… Samples 801 133 x 1 sample per patient 86 x 2-3 samples per patient 75 x 4-13 samples per patient Virus isolations 576 (86 % pos.) C2V5 sequences 2581 of 256 samples Protease sequences 1013 of 114 samples Western blot 477 all positive CCR5-Genotype 278 of 294 CCR+/CCR+: 238 CCR+/CCR-: 40 16x no DNA Paul-Ehrlich-Institut Barbara Schnierle - Christel Kamp 3/12
Paul-Ehrlich-Institut Our data basis Bundesamt für Sera und Impfstoffe Comprehensive longitudinal patient data allow for → an assessment of the evolutionary dynamics of HIV infections of patients with distinct characteristics (case studies) → an assessment of evolutionary patterns of HIV infections (in general, in specific subpopulations/conditions etc.) → Goal: Refining data to information and predictive models! ∑ ?! ∫ …TTTACACAACAGGACAAA… Paul-Ehrlich-Institut Barbara Schnierle - Christel Kamp 4/12
Paul-Ehrlich-Institut Our data basis Bundesamt für Sera und Impfstoffe Comprehensive longitudinal patient data allow for → an assessment of the evolutionary dynamics of HIV infections of patients with distinct characteristics: a stem cell transplanted patient → an assessment of evolutionary patterns of HIV infections (in general, in specific subpopulations/conditions etc.) → Goal: Refining data to information and predictive models! ∑ ?! ∫ …TTTACACAACAGGACAAA… Paul-Ehrlich-Institut Barbara Schnierle - Christel Kamp 5/12
Paul-Ehrlich-Institut HIV and stem cell transplantation Bundesamt für Sera und Impfstoffe Learn about HIV from exceptional circumstances… Importance of target cells? Interactions between HIV and immune system? How is HIV affected by a “reset” of the immune system? Paul-Ehrlich-Institut Barbara Schnierle - Christel Kamp 6/12
Paul-Ehrlich-Institut HIV and stem cell transplantation Bundesamt für Sera und Impfstoffe Learn about HIV from exceptional circumstances…another SCT patient SCT Nov. 2 nd , 2005 HIV specific antibodies Therapy Therapy Paul-Ehrlich-Institut Barbara Schnierle - Christel Kamp 7/12
Paul-Ehrlich-Institut HIV and stem cell transplantation Bundesamt für Sera und Impfstoffe SCT patient non-transplanted patient SCT Therapy Therapy Virus diversity is large diminished after SCT! Paul-Ehrlich-Institut Barbara Schnierle - Christel Kamp 8/12
Paul-Ehrlich-Institut Our data basis Bundesamt für Sera und Impfstoffe Comprehensive longitudinal patient data allow for → an assessment of the evolutionary dynamics of HIV infections of patients with distinct characteristics: a stem cell transplanted patient → an assessment of evolutionary patterns of HIV infections (in general, in specific subpopulations/conditions etc.) → Goal: Refining data to information and predictive models! ∑ ?! ∫ …TTTACACAACAGGACAAA… Paul-Ehrlich-Institut Barbara Schnierle - Christel Kamp 9/12
Paul-Ehrlich-Institut Phenotype testing vs. in silico prediction Bundesamt für Sera und Impfstoffe Goal: Refining data to information and predictive models! ∑ ?! ∫ …TTTACACAACAGGACAAA… * * * * * AMD3100 AMD3100 geno2pheno * CCR5 CXCR4 CXCR4 PSSM * * * IsnoR5 PBMC or T cell line Paul-Ehrlich-Institut Barbara Schnierle - Christel Kamp 10/12
Paul-Ehrlich-Institut Phenotype testing vs. in silico prediction Bundesamt für Sera und Impfstoffe Samples from Phenotype testing in silico prediction SCT patient IsnoR5 PBMC PBMC+AMD3100 PSSM Geno2pheno (X4) (R5/X4) (R5) (score ~0,94) Nr. 786 - + + X4 X4 Nr. 801 - - - R5 X4 Nr. 806 - + + X4 X4 Nr. 845 - + + X4 X4 Validation and training of in silico models! Paul-Ehrlich-Institut Barbara Schnierle - Christel Kamp 11/12
Paul-Ehrlich-Institut Thank you… Bundesamt für Sera und Impfstoffe PEI: Birgit Krause Albrecht Werner Britta Meyé Dorothea Binninger-Schinzel Gudrun Winskowsky Daniela Müller Uni-Klinikum Frankfurt: Reinhard Brodt Timo Wolf Universität Köln: Rolf Kaiser CSISP/Advanced Centre for Research in Public Health: Ignacio González Bravo Paul-Ehrlich-Institut Barbara Schnierle - Christel Kamp 12/12
Paul-Ehrlich-Institut HIV and stem cell transplantation Bundesamt für Sera und Impfstoffe Humoral immune response to HIV-1 gp160 gp120 p66 gp41 p24 p17 Serum control HIV-2 positive control Weak reaction negative control + 105 + 119 + 180 + 384 + 18 + 20 + 27 + 34 + 35 + 43 + 91 - 92 - 61 - 10 9 - days relative to transplantation Paul-Ehrlich-Institut Barbara Schnierle - Christel Kamp 13/12
Paul-Ehrlich-Institut Phenotype testing vs. in silico prediction Bundesamt für Sera und Impfstoffe Samples from Phenotype testing in silico prediction SCT patient IsnoR5 PBMC PBMC+AMD3100 PSSM Geno2pheno (X4) (R5/X4) (R5) (score ~0,94) Nr. 786 - + + X4 X4 Nr. 801 - - - R5 X4 Nr. 806 - + + X4 X4 Nr. 810 - - - X4 X4 Nr. 812 - - - X4 X4 Nr. 815 - - - X4 X4 Nr. 818 - - - X4 X4 Nr. 845 - + + X4 X4 Nr. 886 - - - X4 X4 Validation and training of in silico models! Paul-Ehrlich-Institut Barbara Schnierle - Christel Kamp 14/12
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