# Complementing broadly neutralizing antibodies and autologous responses to restrict virus escape and durably suppress HIV-1

> **NIH NIH U01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $1,481,429

## Abstract

Project Summary/Abstract.
Advances in B cell biology and molecular virology have enabled the discovery, characterization, and commercial
development of several classes of broadly neutralizing antibodies (bnAbs), with applications for prevention,
treatment, and cure of HIV disease are under study. Yet, virus resistance remains the central vulnerability
of effective bnAb use. This application proposes to address the problem of bNAb escape by rationally selecting
combination bNAb therapy that limits virus escape. We propose to apply lessons from the successful
development of combination antiretrovial therapy (cART), whereby bidirectional phenotypic antagonism was
exploited. Our multidisciplinary team has secured plasma virus or virus sequences from recent or ongoing
prevention and treatment studies of VRC01-class CD4 binding site (CD4bs)-targeting monotherapy, as well as
combination therapy with V3 glycan-targeting (Table 1). We will leverage these unique samples to map the in
vivo escape pathways of virus replicating in the presence of sub-suppressive levels of these clinically relevant
bNAbs (Aim 1). Using the evolving escape variants, we will identify putative complementary bNAbs with
maintained or inverse antibody sensitivities from rationally designed panels of candidate bNAbs (Aim 1). We will
then characterize the autologous neutralizing antibody (anAb) response in the treatment cohorts, to determine
the capacity of anAbs to impede virus escape from administered bNAbs (Aim 2). Finally, we will test the most
promising complementary bNAbs to restrict virus escape in vivo in a validated barcoded TF SHIV/NHP model
(Aim 3). Our scientific premise is that in vivo mapping of virus escape from bNAbs, identification of
complementary bNAbs, defining the role of autologous antibodies, and rigorous in vivo testing in an authentic
NHP model will elucidate basic mechanisms of virus resistance to bNAbs and inform more effective use of bNAbs
across the HIV prevention, treatment and cure fields. If accomplished we will (i) have defined the sensitivities of
escaped viruses from clinical trials to alternate bNAbs, (ii) identified bNAbs that cannot mutually escape using
the same pathway, (iii) defined the role of anAbs in bnAb escape and (iv) tested the ability of complementary
bnAbs to improve therapy in an authentic NHP model.

## Key facts

- **NIH application ID:** 10469169
- **Project number:** 1U01AI169767-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Katharine June Bar
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,481,429
- **Award type:** 1
- **Project period:** 2022-04-11 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469169

## Citation

> US National Institutes of Health, RePORTER application 10469169, Complementing broadly neutralizing antibodies and autologous responses to restrict virus escape and durably suppress HIV-1 (1U01AI169767-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10469169. Licensed CC0.

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