# Structure-function studies of the membrane-interacting domains of HIV-1 Env spike

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $792,780

## Abstract

Project Summary
 The first critical step of HIV-1 infection is fusion of viral and target cell membranes mediated by envelope
glycoprotein (Env). The mature Env spikes [trimeric (gp160)3, cleaved to (gp120/gp41)3] are the sole antigens
on the virion surface. Conformational changes in gp120 when triggered by binding to receptor (CD4) and co-
receptor (e.g., CCR5 or CXCR4) lead to a cascade of refolding events in gp41, and ultimately to membrane
fusion. Vast amount of structural information is available for the ectodomain of Env, but much less is known
regarding its transmembrane domain (TMD) and its membrane-proximal (MP) regions, including the membrane
proximal external region (MPER) and the cytoplasmic tail (CT). We recently made an unexpected discovery
that truncation of the CT domain drastically reshapes the antigenic surfaces of the Env ectodomain on the
other side of the membrane. Deep understanding of the physical coupling (conformation and/or dynamics)
between the CT and the ectodomain mediated by the TMD may guide Env-based immunogen design to induce
broadly neutralizing antibodies (bnNabs). We thus hypothesize that the membrane-interacting domains
(MPER, TMD and CT) of HIV-1 Env adopt defined structures which are critical for its stability, function
and antigenicity. We have already completed a TMD structure at the atomic resolution using the state-of-the-
art NMR technology. When reconstituted in bicelles that mimic lipid bilayer, the TMD forms a well-ordered
trimer mainly stabilized by a tightly packed hydrophilic core near its C-terminal end that can potentially be
influenced by the CT domain. In this application, we plan to combine structural biology approaches and
functional assays to elucidate the roles of the membrane-interacting domains of HIV-1 Env. We will purse the
following specific aims: 1) we will investigate TMD assembly of HIV and SIV Env and possible interaction with
the fusion peptide; 2) we will provide structural information for the MP regions of Env in the context of
membrane; 3) we will elucidate the role of the membrane-interacting domains of Env in its stability, function
and antigenicity; 4) we will design trimer immunogens to mimic the native and functional HIV-1 Env spike..

## Key facts

- **NIH application ID:** 9899171
- **Project number:** 5R01AI127193-05
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** JAMES Jeiwen CHOU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $792,780
- **Award type:** 5
- **Project period:** 2016-05-20 → 2021-07-11

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899171

## Citation

> US National Institutes of Health, RePORTER application 9899171, Structure-function studies of the membrane-interacting domains of HIV-1 Env spike (5R01AI127193-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9899171. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*