# Next Generation Broadly Neutralizing Antibodies to Clear HIV-1 Reservoir

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $778,402

## Abstract

Project summary
HIV-1 curing is one of the top priorities for AIDS interventions. The recent isolation of many potent
and broadly neutralizing antibodies (bNAbs) against HIV envelope glycoproteins (Env) offers
great opportunities for exploring their potential as passively administered agents to treat
established infections. The protective efficacy of bNAbs is primarily mediated by their extremely
high capacity to inhibit virus infectivity and cell-cell virus spread (neutralization), as well as their
ability to facilitate the killing of infected cells that express the cognate Env antigens on the cell
surface through antibody-dependent cell-mediated cytotoxicity (ADCC) and to form antibody-virus
immune complexes leading to viral clearance. Unfortunately, the outcome of the most recent
clinical trials with bNAb as therapeutic agent demonstrated that the antigenically diverse and
persistently evolving HIV-1 Env can rapidly acquire mutations that evade bNAbs administered as
single agents. While simultaneously targeting distinct cognate epitopes by physically
combining multiple bNAbs can result in virtually 100% virus coverage, the use of a “single” agent
consisting of these multiple functional binding moieties is preferred for both regulatory and
manufacturing purposes, in addition to the potential of augmented potency resulting from the
increased avidity through bi- or multi- valence Env binding and possible synergistic effect between
bNAbs. In addition, a recent study demonstrated in non-human primate model that in conjunction
with bNAb therapy, CD8+ cytolytic T cells can effectively control virus rebound after the cessation
of anti-viral therapy. Therefore, it is timely to engineer therapeutic agent that can effectively bridge
the infected cells and the cytolytic T cells to mediate the killing of infected cells. Furthermore,
previous studies established that modifications in the antibody Fc regions that increase their
abilities to mediate cytotoxicity and extend their half-lives. However, such modifications have not
been well applied to bNAbs for HIV treatment. This study aims to fill in the tremendous knowledge
gap in the field by investigations with the following specific aims: 1) To generate HIV Env bNAbs
with multiple epitope binding moieties possessing improved potency, avidity and breadth by
structure-based design; 2) To engineer bNAbs that will efficiently recruit CD8+ cytolytic T cells to
latently infected CD4+ T cells and kill the infected cells; and 3) To improve Fc region effector
function (ADCC). The overall outcome of this study will advance our basic understanding of
protective immunity against persistent virus infection and contribute to the development of safe
and effective intervention strategies for HIV remission and eradication.

## Key facts

- **NIH application ID:** 10054157
- **Project number:** 5R01AI136756-03
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Qingsheng Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $778,402
- **Award type:** 5
- **Project period:** 2018-11-09 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10054157

## Citation

> US National Institutes of Health, RePORTER application 10054157, Next Generation Broadly Neutralizing Antibodies to Clear HIV-1 Reservoir (5R01AI136756-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10054157. Licensed CC0.

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