VSV-Displayed HIV-1 Envelope Identifies Broadly Neutralizing Antibodies Class-Switched to IgG and IgA

Cell Host Microbe. 2020 Jun 10;27(6):963-975.e5. doi: 10.1016/j.chom.2020.03.024. Epub 2020 Apr 20.

Abstract

The HIV-1 envelope (Env) undergoes conformational changes during infection. Broadly neutralizing antibodies (bNAbs) are typically isolated by using soluble Env trimers, which do not capture all Env states. To address these limitations, we devised a vesicular stomatitis virus (VSV)-based probe to display membrane-embedded Env trimers and isolated five bNAbs from two chronically infected donors, M4008 and M1214. Donor B cell receptor (BCR) repertoires identified two bNAb lineages, M4008_N1 and M1214_N1, that class-switched to immunoglobulin G (IgG) and IgA. Variants of these bNAbs reconstituted as IgA demonstrated broadly neutralizing activity, and the IgA fraction of M1214 plasma conferred neutralization. M4008_N1 epitope mapping revealed a glycan-independent V3 epitope conferring tier 2 virus neutralization. A 4.86-Å-resolution cryogenic electron microscopy (cryo-EM) structure of M1214_N1 complexed with CH505 SOSIP revealed another elongated epitope, the V2V5 corridor, extending from V2 to V5. Overall, the VSVENV probe identified bNAb lineages with neutralizing IgG and IgA members targeting distinct sites of HIV-1 Env vulnerability.

Keywords: Env immunogen design; HIV vaccine; IgG to IgA; V2V5 corridor; antibody class-switch; broadly neutralizing antibody; cryo-EM.

MeSH terms

  • AIDS Vaccines
  • Antibodies, Neutralizing / immunology
  • Broadly Neutralizing Antibodies / immunology*
  • Cryoelectron Microscopy
  • Epitope Mapping
  • Epitopes / immunology
  • Female
  • HEK293 Cells
  • HIV Antibodies / chemistry
  • HIV Antibodies / genetics
  • HIV Antibodies / immunology*
  • HIV Antibodies / metabolism
  • HIV Infections / virology
  • HIV-1 / immunology
  • HeLa Cells
  • Humans
  • Immunoglobulin A / immunology*
  • Immunoglobulin G / immunology*
  • Models, Molecular
  • Protein Conformation
  • Sequence Alignment
  • Vesiculovirus
  • Viral Envelope / immunology*
  • env Gene Products, Human Immunodeficiency Virus / chemistry
  • env Gene Products, Human Immunodeficiency Virus / immunology*

Substances

  • AIDS Vaccines
  • Antibodies, Neutralizing
  • Broadly Neutralizing Antibodies
  • Epitopes
  • HIV Antibodies
  • Immunoglobulin A
  • Immunoglobulin G
  • env Gene Products, Human Immunodeficiency Virus