# Conformational Landscape of the HIV-1 Envelope Glycoproteins

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2021 · $657,190

## Abstract

PROJECT SUMMARY/ABSTRACT
The entry of human immunodeficiency virus (HIV-1) into host cells is mediated by the envelope glycoprotein
(Env) trimer. The Env trimer consists of three gp120 exterior glycoproteins non-covalently associated with
three gp41 glycoproteins, which are anchored in the viral membrane and which possess long (~145-residue)
cytoplasmic tails. As the only virus-specific molecule on the viral surface, Env is the major target for host
neutralizing antibodies. Env conformational flexibility is essential for virus entry and also contributes to the
ability of HIV-1 to evade the host antibody response. During virus entry, the binding of gp120 to the receptors,
CD4 and CCR5/CXCR4, triggers conformational changes in the metastable Env that ultimately result in gp41-
mediated fusion of the viral and target cell membranes. The HIV-1 Env on virions potentially samples at least
three conformations: a “closed” pretriggered conformation (State 1), an “open” CD4-bound conformation (State
3), and an intermediate “partially open” conformation (State 2). Prior to receptor engagement, the State-1 Env
conformation is energetically favored, rendering primary HIV-1 strains relatively resistant to the binding of
potentially neutralizing antibodies. CD4 binding drives Env from State 1 to State 2 and then into State 3, the
prehairpin intermediate. Binding of the State-3 Env to the CCR5 or CXCR4 coreceptor promotes the formation
of the highly stable gp41 six-helix bundle, resulting in the fusion of the viral and target cell membranes.
Multiple observations indicate that the State-1 Env conformation is metastable and easily disrupted by
alteration of Env sequences or extraction of Env from a membrane environment. Indeed, stabilized soluble
gp140 trimers or detergent-solubilized Env trimers for which detailed structures are available have been shown
to adopt a State-2-like conformation! The proposed work will address our currently incomplete understanding
of the State-1 Env conformation. How does HIV-1, despite its tremendous variability, maintain a State-1 Env
conformation? We have previously shown that changes in multiple Env amino acid residues can disrupt the
State-1 conformation. In the proposed studies, we will identify naturally polymorphic Env residues that, when
changed, stabilize the functional State-1 conformation. We will evaluate how State-1-stabilizing and State-1-
destabilizing changes in Env interact to determine viral phenotypes. One focus of these studies will be the
relationship between the conformation of the gp41 membrane-proximal external region (MPER) and the
conformation of the rest of the Env ectodomain.
The metastability of the State-1 Env conformation impedes its presentation to the host immune system during
natural HIV-1 infection and following vaccination. The proposed studies will inform efforts to produce purified
HIV-1 Env trimers stabilized in a State-1 conformation, which serves as the major target of broadly neutralizing
a...

## Key facts

- **NIH application ID:** 10248854
- **Project number:** 2R01AI124982-06A1
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** JOSEPH G SODROSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $657,190
- **Award type:** 2
- **Project period:** 2016-02-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10248854

## Citation

> US National Institutes of Health, RePORTER application 10248854, Conformational Landscape of the HIV-1 Envelope Glycoproteins (2R01AI124982-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10248854. Licensed CC0.

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