# Quantifying the fitness cost of HIV-1 resistance to broadly neutralizing antibodies

> **NIH NIH R01** · GEORGE WASHINGTON UNIVERSITY · 2021 · $712,648

## Abstract

PROJECT SUMMARY/ABSTRACT:
Immunotherapy with monoclonal antibodies (mAbs) has been successful in settings such as autoimmunity and
cancers, and therefore, treatment options with antibodies especially re-designed molecules based on broadly
neutralizing antibodies (bNAbs) should be explored in the context of HIV-1. A caveat is that HIV-1 has the ability
to rapidly escape from antibodies by generating mutations in its variable env gene. Therefore, there is an urgent
need to gain insight into HIV-1 escape from bNAbs to aid in more effective combination antibody strategies to
be used towards HIV-1 therapy, cure and prevention. As bNAbs are already being tested in clinical trials, it is
imperative that optimal antibody combinations are evaluated not only for their neutralization capability but also
their ‘ease of escape’ by diverse viruses. The overall objective of this proposal is to measure the ability of
genetically diverse strains of HIV to escape from broadly neutralizing antibodies and design an antibody cocktail
capable of restricting escape. To accomplish this goal, Dr. Lynch, who is an expert in HIV-1 escape from bNAbs
has put together a collaborative team for an interdisciplinary approach using molecular virology (Dr. Lynch),
computational methods (Drs. Barton and Fischer) and a humanized-mouse model (Dr. Klein) to study HIV-1
escape. Our central hypothesis is that HIV-1 escape from combination bNAbs will be limited when the
mutations required to escape all bNAbs exert the maximum replicative fitness cost across diverse
viruses and, therefore, replication cannot easily be restored through compensatory mutations. We will
test this hypothesis by (i) defining a library of viable escape pathways for single bNAbs in diverse viruses with in
vitro and in vivo approaches, (ii) determining the fitness cost or “ease” of escape for virus-bNAb pairings
bioinformatically, and (iii) identifying the optimal combination of antibodies that maximize fitness costs of
resistance in diverse HIV-1 subtypes and testing this combination in vitro and in vivo. Our outcome will be the
identification of optimal combination antibody cocktails to limit the ability of diverse HIV-1 viruses to escape from
antibody pressure. These findings will inform all clinical trials using bNAbs or bNAb-based molecules, and
ultimately, these studies will define a rational pipeline to characterize antibody escape pathways in the future.

## Key facts

- **NIH application ID:** 10163128
- **Project number:** 5R01AI152770-02
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Rebecca Marie Lynch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $712,648
- **Award type:** 5
- **Project period:** 2020-05-13 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10163128

## Citation

> US National Institutes of Health, RePORTER application 10163128, Quantifying the fitness cost of HIV-1 resistance to broadly neutralizing antibodies (5R01AI152770-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10163128. Licensed CC0.

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