HIV Attachment and Entry: Pursuing a Challenging Target

Introduction

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.

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

Key Viral Protein for HIV Entry

HIV-1 Immune Pressure and Evasion

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

HIV-1 Env Entry Pathway Contains Additional Prefusion States

Understand Entry and Immune Evasion With Atomic-Level Insights

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

Outline

Link Ligand-Induced States to smFRET Measurements

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

Functional Env Trimer Transitions Between 3 Prefusion Conformation States

State 1 Was Preferentially Recognized by Most Broadly Neutralizing Antibodies

Determination of Env Trimer Structure Used 2 Antibodies for Crystallization

Initial Interaction of CD4 With the HIV-1 Env Trimer

Measurement of smFRET Directly on Soluble Env Trimers

Insights on Structure of Env Trimers

Structural Transformation: State 2 to State 3

Summary: HIV-1 Env Structure

Outline

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

Entry Inhibitors and Targets

Fostemsavir (BMS-663068)

Fostemsavir: BRIGHTE Phase 3 Study

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

Lattice-Chaperone Strategy: Mutations for Improvement

Summary: Chaperone Mutations for Improvement

New Lattice Appears to Be Improved

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

Co-Crystal Structures Show Potential Additional Functional Group

Structural "Freezing" by Temsavir Binding

Summary: Small Molecule Entry Inhibitors

Concluding Remarks

Abbreviations