# Broadly neutralizing antibody combinations with single virions in HIV+ plasma

> **NIH NIH R56** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $386,250

## Abstract

Recently discovered broadly HIV-neutralizing antibodies (bnAbs) are being actively investigated for HIV/AIDS
treatment, functional cure and/or prevention. A variety of such bnAbs are known and classified according to their
epitopes clusters on the HIV envelope (Env). Rigorous preclinical studies evince potential advantages of
engineered bnAbs over currently used antiretroviral drugs (ARVs); including infrequent administration, lower risk
of side effects and genotoxicity, capacity to target latent HIV reservoirs, promotion of host antiviral immune
responses, and insensitivity to conventional ARV resistance. Currently, the major obstacle for realizing the
clinical potential of single bnAbs is that all of them exhibit limits in covering epitope variability, which allows virus
escape. One logical mitigation strategy is to utilize combinations of three bnAbs, each targeting a distinct epitope
cluster. Combinations that promote extensive concurrent binding of bnAbs to the same targets (virions or trimers)
in plasma virus populations are expected to be especially escape resistant. Yet whether and how this goal can
be obtained for HIV prevention or therapy remains unclear. Conventional neutralization assays do not directly
measure bnAb-virion binding but have shown that combining bnAb classes improves breadth and potency.
Models predict that bnAb class combinations can act collectively on a single virus strain. However, clinical trials
suggest a more complex picture. Several trials have tested combined bnAbs, but sustained suppression of
viremia has not yet been demonstrated. Collectively, these findings introduce several important questions
regarding concurrent bnAb binding in vivo: Are certain bnAb class combinations distinguishable as “superior” in
establishing concurrent virion/trimer binding within major fractions of plasma virus swarms? How consistently
does such desirable coverage occur across individuals and subtypes? Does HIV+ human plasma contain
immunoreactive particles (exosomes, immature virions); circulating anti-Env antibodies or other factors that
perturb desirable concurrent binding patterns? Goal of the project is to answer these questions by direct analyses
of bnAb-virion interactions in native plasma. Our hypothesis is that this unique endeavor can be accomplished
by novel quantitative single molecule and fluorescence correlation spectroscopy (FCS) detection methods
applied to plasma virions in situ. Two Specific Aims are: Aim 1. Establish the immunoreactivity patterns of bnAb
combinations against single virions or envelope trimers; Aim 2. Characterize interactions of bnAbs and bnAb
combinations with single virions in HIV+ plasma. Project output will be an unprecedented tier of data informing
the nature of combined bnAb action in vivo and prospects for triple bnAb combinations to counter HIV escape.
Our data will uniquely define principles, limits, and opportunities in using bnAb combinations to target circulating
virions in the HIV+ ...

## Key facts

- **NIH application ID:** 10655874
- **Project number:** 1R56AI172487-01
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Krishanu Ray
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $386,250
- **Award type:** 1
- **Project period:** 2022-08-18 → 2023-01-22

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10655874

## Citation

> US National Institutes of Health, RePORTER application 10655874, Broadly neutralizing antibody combinations with single virions in HIV+ plasma (1R56AI172487-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10655874. Licensed CC0.

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