# Early interventions at ART initiation to reduce the HIV-1 reservoir and enhance adaptive immune responses

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $694,301

## Abstract

Increasing efforts are being made to understand whether early intervention after HIV-1 infection can enable long-
term viral control and reduction of the viral reservoir through the preservation of HIV-1-specific immune
responses. Recently, the pioneering eCLEAR phase 1b/2a clinical trial led by MPI SØgaard, found that
administration of the HIV-Env specific broadly neutralizing antibody (bNAb) 3BNC117 at antiviral therapy (ART)
initiation enhanced CD8+ T cell viral immunity and enabled viral control amongst participants harboring
3BNC117-sensitive viruses. However, the mechanisms underlying this outcome remain largely unknown.
Understanding The goal of this collaborative R01 (M Betts, UPenn, B Jones, Weill-Cornell University, and
O. SØgaard, Aarhus University) is to define the mechanisms underlying this protective outcome in order
to inform future development of targeted immunotherapy at ART initiation as an HIV cure strategy. We
hypothesize that the partial success of eCLEAR can be defined in terms of both specific mechanisms of
efficacious CD8+ T-cell responses and of the features selected in remaining reservoir-harboring cells. We will
address this hypothesis in three integrated Aims using samples directly from the eCLEAR study. In Aim 1, we
will define phenotypic, functional, and transcriptomic features of the adaptive T cell immune responses that are
modulated by bNAb treatment at ART initiation (SØgaard). In Aim 2, we will define how the HIV reservoir is
differentially modulated after prolonged ART treatment and within post-therapy viral controllers vs. non-
controllers who received 3BNC117 (Betts). In Aim 3, we will define the ability of CD8+ T cells from eCLEAR
participants who did or did not exhibit post-ART control to mediate viral control in vivo using a novel humanized
mouse model. In addition, we will modulate CD8+ T cell functions within this system to uncover specific control
mechanisms. The anticipated outcomes of our project are i) A comprehensive characterization of the
immunologic and reservoir features associated with the partial efficacy of eCLEAR, ii) Validation of underlying
mechanisms, to guide future iterations of clinical interventions at the time of ART initiation.

## Key facts

- **NIH application ID:** 11017367
- **Project number:** 1R01AI184285-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Michael R Betts
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $694,301
- **Award type:** 1
- **Project period:** 2024-08-19 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11017367

## Citation

> US National Institutes of Health, RePORTER application 11017367, Early interventions at ART initiation to reduce the HIV-1 reservoir and enhance adaptive immune responses (1R01AI184285-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11017367. Licensed CC0.

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