# Defining the impact of glycan-microdomains of the HIV-1 Env glycan shield

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $718,601

## Abstract

ABSTRACT
Human immunodeficiency virus 1 (HIV-1) is a major global pathogen, with 1.7 million new infections in 2019.
The HIV-1 envelope glycoprotein (Env) is the sole virus-surface antigen. Env, a trimer of gp120/gp41 dimer
subunits, is densely glycosylated by N-glycans. For the gp120 subunit, N-glycans contribute over 50% of its
molecular mass and form a protective surface, the so-called “glycan shield”, that interacts with cellular receptors
and the immune system and protects the virus from neutralizing antibodies (nAbs). Recently, the concept of an
“evolving glycan shield” has been proposed, based on the sequence analysis of immune-escape variants that
have lost some potential N-glycosylation sites (NGS) and gained others. Despite significant strides in
understanding the biology of HIV-1 Env, the complexity and function of N-glycans at a molecular level are poorly
understood. Based on our bioinformatics and experimental studies, we recently proposed that the Env glycan
shield may be defined, and analyzed, as distinct structural glycan-microdomains. Using naturally occurring Env
variants of a clade B virus, we analyzed the glycans surrounding the highly conserved N262 glycan, in the so-
called high-mannose patch (HMP) near the apex of the Env trimer. These HMP glycans, comprised of different
combinations of 4 to 6 NGS in the proximity of N262, appear to form a glycan working unit. Based on our
published results and preliminary data, we hypothesize that Env outer domain, gp120 glycan shield, has
structural components that can be defined as distinct structural glycan-microdomains. We propose to
test our hypothesis in different clades of HIV-1 and their immune-escape variants by assessing structural and
functional impacts of a range of N-glycan combinations that comprise Env glycan-microdomains. Specifically,
we propose to determine how different NGS combinations of the N262-anchored HMP-microdomain across
variants and clades influence Env functions (Aim 1), to probe the structural arrangement of different N262-glycan
cluster NGS combinations in the context of functional recombinant Env trimers (Aim 2), and to assess the
functional impacts of other potential glycan-clusters of the HIV-1 Env glycan shield (Aim 3). To accomplish these
goals, we will use a combination of functional, bioanalytical, structural bioinformatics, and molecular dynamics
simulation approaches. The results of these studies will test our proposed hypothesis on the functional impact
of the structural components of the glycan shield, glycan-microdomains, and will determine how the varied
compositions of these microdomains affect the function of the glycan shield. These data will advance our
understanding of the molecular biology of HIV-1 and the factors that impact viral transmission and persistence.
Ultimately, these studies will generate new information about Env vulnerabilities that can be exploited to develop
future therapeutic approaches.

## Key facts

- **NIH application ID:** 10258291
- **Project number:** 1R01AI162236-01
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** JAN NOVAK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $718,601
- **Award type:** 1
- **Project period:** 2021-04-10 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10258291

## Citation

> US National Institutes of Health, RePORTER application 10258291, Defining the impact of glycan-microdomains of the HIV-1 Env glycan shield (1R01AI162236-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10258291. Licensed CC0.

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