# Immunologic control of HIV-1 through combination bNAbs and biologics.

> **NIH NIH U01** · ROCKEFELLER UNIVERSITY · 2022 · $1,667,616

## Abstract

Project Summary
Despite the success of antiretroviral therapy (ART) in suppressing viral replication and preventing disease
progression, HIV-1 persists in a long-lived reservoir of latently infected cells that harbor integrated proviruses
which can be reactivated, resulting in the lifelong requirement of ART. Efforts to identify strategies to eradicate
or induce treatment-free long-term HIV-1 remission are critical. Broadly neutralizing antibodies (bNAbs) differ
from ART in that they can recruit immune effector functions through their Fc domains to accelerate clearance
of viruses and infected cells. In addition, immune complexes are potent immunogens that can foster
development of host immune responses. 3BNC117 and 10-1074 are bNAbs that bind to the CD4 binding site
(CD4bs) and to the base of the V3 loop in HIV-1 envelope gp-120. Both antibodies show exceptional breadth
and potency in vitro, and protect against or suppress infection in animal models. When administered during
early chimeric simian/human immunodeficiency virus (SHIV) infection, 3BNC117 and 10-1074 led to sustained
virologic control in about half of the tested animals. This effect was due to CD8+ T cell mediated control of
viremia, suggesting that the bNAbs exerted immune enhancing effects. In HIV-infected adults, three doses
3BNC117 and 10-1074 over 6 weeks maintained viral suppression for an average of 21 weeks in individuals
harboring antibody-sensitive viruses, including two individuals who continued to maintain viral suppression for
at least 11 months after ART discontinuation. The potential immune modulatory effects of bNAbs are
dependent of the availability of antigen. Fully suppressive ART reduces the frequency of infected cells
expressing envelope to levels that appear to be too low to induce immunity. In contrast, bNAb-mediated viral
suppression may allow sufficient antigen expression to trigger immunologic effects, and these effects are likely
to be enhanced when bNAbs are used in combination with molecules known to modulate immune responses
and induce viral transcription. We propose to test these concepts using N-803, an interleukin-15 superagonist,
which has immune modulatory properties, such as enhancement of antibody-dependent cell-mediated
cytotoxicity, and induces HIV-1 reactivation. This project aims to conduct two clinical studies to evaluate the
antiviral activity of the combination of the long-acting (“LS”) variants of 3BNC117 and 10-1074 in viremic HIV-
infected individuals, and to assess the ability of this long-acting dual-bNAb combination to produce sustained
viral remission when administered with the IL-15 superagonist, N-803, during ART interruption.

## Key facts

- **NIH application ID:** 10197829
- **Project number:** 5U01AI145921-03
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Marina Caskey
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,667,616
- **Award type:** 5
- **Project period:** 2019-07-05 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197829

## Citation

> US National Institutes of Health, RePORTER application 10197829, Immunologic control of HIV-1 through combination bNAbs and biologics. (5U01AI145921-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10197829. Licensed CC0.

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