# High-Definition Characterization of the Persistence and Perturbation of the HIV Reservoir: Project 3

> **NIH NIH P01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $471,572

## Abstract

Abstract
 SAR441236 is a tri-specific HIV-1 broadly neutralizing antibody (bnAb) that combines
the CD4 binding site (CD4bs) specificity of VRC01-LS, the V1/V2 glycan-directed binding of
PGDM1400, and the gp41 MPER binding of 10E8v4 into one antibody molecule (1). This
trispecific bnAb has greater potency and breadth than any single bnAb and provided complete
protection to macaques against intra-rectal challenge by a mixture of SHIVs.
 The advantages of a three-in-one bnAb, when compared to three separate monospecific
bnAbs administered in combination, are the potential to improve efficacy and simplify prevention
and treatment regimens, possibly improving patient adherence. ACTG A5377 is a phase I first-
in-human study of SAR441236 that investigates this novel trispecific bnAb in viremic and
aviremic participants with HIV.
 Administration of an HIV-1 bnAb could affect reservoir dynamics through two
mechanisms: 1) a direct antiviral effect that clears residual virions and infected cells, and/or 2)
indirect effects that improve anti-HIV surveillance and immune function. The scientific premise
of this proposal is that treatment with SAR441236 during suppressed infection selectively
prunes the HIV-1 proviral landscape and affects immune system function, directly or indirectly,
to improve HIV-1 control. The goals of this proposal are to determine if trispecific bnAb
treatment during suppressive ART impacts the HIV-1 provirus landscape and to define what
effects, if any, trispecific bnAb administration has on the immune system and the anti-HIV
immune response.
 We hypothesize that SAR441236 leads to the selective loss of intact provirus variants,
modulates Treg and antigen presenting cell (APC) function, and improves cytolytic immune
responses to HIV-1. Specific Aims of this proposal are to investigate SAR441236 selection
pressure on the HIV-1 reservoir, define the effects of SAR441236 on the peripheral immune
system epigenome, transcriptome and cell surface proteome at single cell resolution, and to
understand the effects of SAR441236 on cytolytic immune responses – CD8+ T cells and NK
cells - to enhance reservoir clearance. Our approaches build on novel technologies to test
previously unexplored hypotheses that are central to understand how treatment with
SAR441236 influences the HIV-1 proviral reservoir and the peripheral immune system.

## Key facts

- **NIH application ID:** 10469113
- **Project number:** 1P01AI169768-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Athe M. Tsibris
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $471,572
- **Award type:** 1
- **Project period:** 2022-07-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469113

## Citation

> US National Institutes of Health, RePORTER application 10469113, High-Definition Characterization of the Persistence and Perturbation of the HIV Reservoir: Project 3 (1P01AI169768-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10469113. Licensed CC0.

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