1. HIV Attachment and Entry: Pursuing a Challenging Target

2. Introduction

3. This program will include a discussion of data that were presented in abstract form. These data should be considered preliminary until published in a peer-reviewed journal.

4. HIV-1 Entry: The First Step in the HIV-1 Life Cycle

5. Key Viral Protein for HIV Entry

6. HIV-1 Immune Pressure and Evasion

7. Overall Outline of Type 1 Fusion Mechanism of HIV-1 Entry Resolved 20 Years Ago

8. HIV-1 Env Entry Pathway Contains Additional Prefusion States

9. Understand Entry and Immune Evasion With Atomic-Level Insights

10. Understand Entry and Immune Evasion with Atomic-Level Insights (cont)

11. Outline

12. Link Ligand-Induced States to smFRET Measurements

13. smFRET Tags in V1-V4 Sample Conformational Flexibility of HIV-1 Env Trimer on Infectious Virus

14. Functional Env Trimer Transitions Between 3 Prefusion Conformation States

15. State 1 Was Preferentially Recognized by Most Broadly Neutralizing Antibodies

16. Determination of Env Trimer Structure Used 2 Antibodies for Crystallization

17. Initial Interaction of CD4 With the HIV-1 Env Trimer

18. Measurement of smFRET Directly on Soluble Env Trimers

19. Insights on Structure of Env Trimers

20. Structural Transformation: State 2 to State 3

21. Summary: HIV-1 Env Structure

22. Outline

23. Inhibitors That Bind to States 1 and 2 Neutralize Primary Isolates; Those That Only Bind State 3 Often Do Not

24. Entry Inhibitors and Targets

25. Fostemsavir (BMS )

26. Fostemsavir: BRIGHTE Phase 3 Study

27. Crystal Structures of HIV-1-Env Trimer With BMS-378806 and Its Derivative, Temsavir

28. Lattice-Chaperone Strategy: Mutations for Improvement

29. Summary: Chaperone Mutations for Improvement

30. New Lattice Appears to Be Improved

31. New Crystal Allows for the Determination of Structures With Trimers From Diverse HIV-1 Strains

32. Co-Crystal Structures Show Potential Additional Functional Group

33. Structural "Freezing" by Temsavir Binding

34. Summary: Small Molecule Entry Inhibitors

35. Concluding Remarks

36. Abbreviations