# How HIV-1 might escape eCD4-lg

> **NIH NIH R21** · SCRIPPS FLORIDA · 2020 · $285,000

## Abstract

PROJECT SUMMARY
The goal of this proposal is to assess how HIV might escape eCD4-Ig, an exceptionally broad and difficult-
to-escape entry inhibitor, using an approach we have recently developed for generating a highly diverse
proviral library. eCD4-Ig is an engineered antibody-like molecule that potently neutralizes all 270 HIV-1,
HIV-2 and SIV isolates that it has been tested against. When expressed by adeno-associated virus (AAV),
eCD4-Ig can completely protect rhesus macaques from multiple high-dose challenges with both SHIV-AD8
and SIVmac239 (Gardner et al., Nature, 2015). Moreover, as we show in preliminary data, AAV-eCD4-Ig
can suppress an established infection in macaques after cessation of antiretroviral therapy. Consistent with
eCD4-Ig's exceptional breadth, our preliminary data also show that escape from eCD4-Ig is considerably
more challenging than from broadly neutralizing antibodies. In fact, cell culture and in vivo efforts to select
HIV-1 and SIV variants fully resistant to eCD4-Ig have so far been unsuccessful, even under the same
conditions in which escape from bNAbs can be readily observed. We have recently developed a novel,
highly parallel method for identifying pathways by which HIV-1 escapes an entry inhibitor. This technique
allows the introduction of a controlled number of mutations into key targeted regions. We have shown that
the library built using this method can be used to rapidly identify viruses resistant to every well-
characterized VRC01-class CD4-binding site antibody (Otsuka et al., PLOS Pathogens, 2018). We propose
to use the same approach to select HIV-1 variants that are fully resistant to eCD4-Ig, and characterize
selected variants for their escape pathways, and their sensitivities to neutralization and ADCC. These
studies will provide insights into whether escape from eCD4-Ig can be anticipated in forthcoming human
trials, clarify the pathways by which such escape might occur, and perhaps suggest antibodies or other
agents that could make such escape less likely.

## Key facts

- **NIH application ID:** 9864038
- **Project number:** 5R21AI145575-02
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Hyeryun Choe
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $285,000
- **Award type:** 5
- **Project period:** 2019-02-05 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9864038

## Citation

> US National Institutes of Health, RePORTER application 9864038, How HIV-1 might escape eCD4-lg (5R21AI145575-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9864038. Licensed CC0.

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