# Structural and dynamic traits underlying phenotypic variation in HIV-1 Env

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2021 · $531,081

## Abstract

We have long been aware of the astounding sequence variation in the HIV-1 envelope glycoprotein (Env)
gene, but the structural and functional implications of this diversity are only beginning to be grasped. Structural
variation in Env impacts its interactions with all key drivers of viral fitness and replication, and this is not
captured by variation in sequence. These differences underlie viral phenotypic traits such as neutralization
sensitivity, tropism, infectivity, and transmissibility. While recent studies have provided detailed structural
information for trimeric Env ectodomain from a range of viral isolates, the structures represent a static, Platonic
ideal of the Env assembly. Under native conditions, HIV Env is a highly dynamic fusion protein complex that
can flicker between antigenically and functionally distinct conformational states. Biophysical studies from our
group and others are providing the first structure-based indications that the propensity for Env to undergo
large-scale dynamic movements is highly isolate-specific in nature. These changes directly impact a given
Env's interactions with biological factors in the host. Here we will apply innovative structural analytical
approaches, including structural mass spectrometry and cryo-EM, to characterize Env diversity and to identify
the consequences of structural variation and dynamics on antibody binding and antigen presentation by the
dendritic cell displayed lectin, DC-SIGN. We have developed an effective approach for purifying the native-like
SOSIP trimers from highly divergent HIV-1 isolates and have demonstrated in preliminary studies that trimers
even from neutralization resistant primary isolates exhibit significant differences in stability, local structural
dynamics of bNAb epitopes, large-scale conformational breathing, and structure. We will characterize
structural dynamic profiles of the Envs from across the neutralization Tier spectrum and from the Global Panel
of resistant viruses, which was composed to be highly representative of circulating neutralization phenotypes.
We will test whether variants that produced favorable immune responses (breadth and potency) exhibit
structural dynamic traits. And we will assess the effect of dynamics on antibody and DC-SIGN reactivity for
diverse viral isolates. An understanding of variation in Env structure and function will provide a foundation for
understanding differences in HIV pathogenicity and viral fitness, and a better understanding of how the
immune system grapples with this extremely variable antigen. Progress in these areas will inform our
understanding of HIV evolution, and may help guide development of Env-based vaccines and immunogens.

## Key facts

- **NIH application ID:** 10186690
- **Project number:** 5R01AI140868-03
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Kelly Keisen Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $531,081
- **Award type:** 5
- **Project period:** 2019-07-02 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10186690

## Citation

> US National Institutes of Health, RePORTER application 10186690, Structural and dynamic traits underlying phenotypic variation in HIV-1 Env (5R01AI140868-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10186690. Licensed CC0.

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