HIV-1 Antibodies

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HIV-1 Antibodies

  1. 1. by tedro senalLE re ab P c nac homiércoles 4 de abril de 12
  2. 2. miércoles 4 de abril de 12
  3. 3. HIV-1 Membrane CD4 gp120 trimer Helper T-cell CCR40 Membrane co-receptormiércoles 4 de abril de 12
  4. 4. The majority of antibodies that target gp120 don’t neutralize HIVmiércoles 4 de abril de 12
  5. 5. The majority of antibodies that target gp120 don’t neutralize HIV CD4 Binding Sitemiércoles 4 de abril de 12
  6. 6. The majority of antibodies that target gp120 don’t neutralize HIV Glycosylation CD4 Binding Sitemiércoles 4 de abril de 12
  7. 7. The majority of antibodies that target gp120 don’t neutralize HIV GlycosylationVariable Loops CD4 Binding Sitemiércoles 4 de abril de 12
  8. 8. Antibodies are multi-domain proteins secreted by B cells Light chain Light chain Heavy Heavy chain chainmiércoles 4 de abril de 12
  9. 9. Antibodies are multi-domain proteins secreted by B cellsmiércoles 4 de abril de 12
  10. 10. Antibodies are multi-domain proteins secreted by B cells VL VL VH VHmiércoles 4 de abril de 12
  11. 11. Antibodies are multi-domain proteins secreted by B cells VL CL VL CL VH VH CH CHmiércoles 4 de abril de 12
  12. 12. Antibodies are multi-domain proteins secreted by B cells VL CL VL CL VH VH antigen CH CH binding sitesmiércoles 4 de abril de 12
  13. 13. Antibody-encoding genes get randomly rearranged in B cells to increase diversity Germ Line DNA Same for all cellsmiércoles 4 de abril de 12
  14. 14. Antibody-encoding genes get randomly rearranged in B cells to increase diversity Variable Constant Germ Line DNA Same for all cellsmiércoles 4 de abril de 12
  15. 15. Antibody-encoding genes get randomly rearranged in B cells to increase diversity Variable Constant Germ Line DNA Same for all cells Rearranged DNA Unique to each B cell (allele)miércoles 4 de abril de 12
  16. 16. Antibody-encoding genes get randomly rearranged in B cells to increase diversity Variable Constant Germ Line DNA Same for all cells Rearranged DNA Unique to each B cell (allele) mRNA2,644,240 potential combinationsmiércoles 4 de abril de 12
  17. 17. B cells undergo fast natural selection, which further increases diversitymiércoles 4 de abril de 12
  18. 18. B cells undergo fast natural selection, which further increases diversity B cells proliferate with high mutation ratemiércoles 4 de abril de 12
  19. 19. B cells undergo fast natural selection, which further increases diversity B cells proliferate with high mutation rate Follicular Dendritic Cells select for binding affinitymiércoles 4 de abril de 12
  20. 20. Effective antibodies differ on sequence but share similar structuresmiércoles 4 de abril de 12
  21. 21. Effective antibodies differ on sequence but share similar structures VHeavy VLightmiércoles 4 de abril de 12
  22. 22. Effective antibodies differ on sequence but share similar structures VHeavy VLightmiércoles 4 de abril de 12
  23. 23. Effective antibodies differ on sequence but share similar structures VHeavy VLightmiércoles 4 de abril de 12
  24. 24. Effective antibodies differ on sequence but share similar structures VHeavy VLight Same germ line allelemiércoles 4 de abril de 12
  25. 25. Similar binding suggests convergent evolution Mature gp120 Germ Shared Line Epitope Paratopemiércoles 4 de abril de 12
  26. 26. 110K reads of HC from a single donor # Reads Sequence Identity with PG04 (%) Germ line divergence (%)miércoles 4 de abril de 12
  27. 27. Sequencing reveals that divergent antibodies are rare 110K reads of HC from a single donor # Reads Sequence Identity with PG04 (%) Germ line divergence (%)miércoles 4 de abril de 12
  28. 28. Sequencing reveals that neutralizing antibodies are divergent 110K reads of HC from a single donor Sequence Identity with Effective Non-effective PG04 (%) Germ line divergence (%)miércoles 4 de abril de 12
  29. 29. Sequencing reveals maturation lineages 110K reads of HC from a single donor Sequence Same CDR H3 Family Identity with PG04 (%) Germ line divergence (%)miércoles 4 de abril de 12
  30. 30. Sequencing reveals maturation lineages 110K reads of HC from a single donor Sequence Same CDR H3 Family Identity with PG04 (%) Good Neutralizer Germ line divergence (%)miércoles 4 de abril de 12
  31. 31. Cross-donor phylogenetic analysis can identify neutralizing antibodiesmiércoles 4 de abril de 12
  32. 32. Cross-donor phylogenetic analysis can identify neutralizing antibodies High performing antibodies from other patientsmiércoles 4 de abril de 12
  33. 33. Cross-donor phylogenetic analysis can identify neutralizing antibodiesmiércoles 4 de abril de 12
  34. 34. gp140 Cross-donor phylogenetic analysis can identify neutralizing 23 mutations antibodies germ line 41 mutations 56 mutations 93 mutations VRC03 High Performingmiércoles 4 de abril de 12
  35. 35. High performing intermediates could form the basis of an effective HIV vaccinemiércoles 4 de abril de 12

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