Exploring the membrane-related components of HIV-1 Env for immunogen design

Summary
Structural insights from our recent work provide a strong scientific premise for exploring the membrane-related
components of HIV-1 envelope glycoprotein (Env), including the membrane proximal external region (MPER),
the transmembrane domain (TMD) and the cytoplasmic tail (CT), for vaccine development. Our data indicate
that all these regions influence the stability and antigenicity of the Env ectodomain. Major broadly neutralizing
antibody (bnAb) epitopes on HIV-1 Env include CD4 binding site, V1V2-glycan, V3-glycan, the fusion
peptide/gp120-gp41 interface and the MPER. The optimal presentation of these epitopes, critical for their
antigenicity and immunogenicity, depends on the Env trimer organization and conformation. Recently, the fusion
peptide-based immunogens have induced robust cross-clade neutralizing responses in animal models,
suggesting that bnAbs may be elicited by vaccination. In this research project, our central hypothesis is that
rationally designed HIV-1 Env immunogens in different conformations with various degrees of bnAb epitope
exposure induce different B cell responses, which may lead to production of diverse bnAbs in animal models
and to new strategies for HIV-1 vaccine immunogen design. The research team is formed by a group of
outstanding investigators with diverse yet complementary expertise to carry out the proposed studies. This group
has extensive experience in protein engineering, production and characterization, in B cell biology and
vaccinology in animal models, and in detailed analysis of vaccine-elicited antibody responses. The group
members have an extensive history of working together on HIV-1 and SARS-CoV-2 related projects. The team
will capitalize on the newly determined structures of the membrane-related components of HIV-1 Env to develop
two innovative immunogen-design strategies: (1) soluble Env trimer immunogens and (2) membrane-bound
intact Env trimer immunogens. We propose two Specific Aims to test the hypothesis: Aim 1. We will design,
characterize and produce Env-based immunogens in both the protein and mRNA forms and perform structural
studies of Env-based immunogens and their complexes with antibodies. Aim 2. We will evaluate immunogenicity
of novel Env-based protein immunogens and mRNA vaccines in VelocImmune human antibody mice.

Grant Number: 5R01AI174938-03
NIH Institute/Center: NIH
Principal Investigator: Bing Chen