# The barcode project: a strategy to track the early naïve reservoir

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $783,206

## Abstract

Memory CD4+ T cells are believed to be the primary reservoir for HIV; however, emerging evidence suggests
an important role for naïve CD4+ T cells. Specifically, sequencing studies suggest the naïve reservoir
contributes substantially to the intact HIV reservoir in chronic progressors, but is practically absent in elite
controllers. While the naïve reservoir is small, it may have outsized effects on the overall reservoir since we
find the naïve reservoir repopulates the memory based on preliminary clone tracking studies. Objective: The
long-term goal is to dissect the role of the naïve reservoir on the overall reservoir in acutely infected individuals
and in a primary model of latency. We will first determine the extent and frequency of naïve infection in acutely
treated individuals. The naïve reservoir has been understudied in this population, but as early ART initiation
becomes more frequent, it is essential to understand the consequences on the overall reservoir. We
hypothesize that the naïve reservoir may be a good predictor of overall reservoir decay. Premise: Underlying
this hypothesis is the idea that the naïve reservoir has a unique ability to provide a long-lived relatively safe
harbor for proviruses due to their relative resistance to immune clearance, while the memory reservoir is more
prone to express HIV and to experience CD8 clearance. Aims: We will determine the contribution of infected
naïve T cells to reservoir dynamics in acutely treated individuals (Aim1) and present a novel ex vivo model to
test the underlying hypothesis behind the mechanism of naïve's contribution (Aim2). Design and Methods: In
both aims, we will measure reservoir size, diversity, clonality, proviral orientation and their dynamics over time
using proviral sequencing and a novel integration site sequencing. To avoid limiting dilution, we developed
methods utilizing Primer-ID to link barcoded proviral sequences to their integration sites. Our optimized model
with barcode tracking uniquely enables us to follow the fate of individual infected naïve T cells. This approach
reveals distinct properties of the naïve reservoir related to its reactivation potential as well as its response to
cognate antigen, LRAs and CD8s. A critical innovation of our model is the ability to track specific subsets under
various conditions that perturb the reservoir. In Aim3, we use the data generated from restricted infections
(Aim2) to dissect the role of naïve and memory infection using mathematical models and then compare the
effect of the naïve reservoir on HIV dynamics in acutely treated individuals from Aim1. We envision this work
will show that naïve infection is fundamental to a formidable reservoir and will ultimately provide a useful
preclinical model for evaluating mechanisms of persistence and future therapies. We will evaluate the effect of
various LRAs and CD8s on the naïve versus memory reservoir to provide a more thorough mechanistic
understanding of the naïve reservoir....

## Key facts

- **NIH application ID:** 11063903
- **Project number:** 7R01AI176952-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Una T O'Doherty
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $783,206
- **Award type:** 7
- **Project period:** 2024-03-31 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11063903

## Citation

> US National Institutes of Health, RePORTER application 11063903, The barcode project: a strategy to track the early naïve reservoir (7R01AI176952-02). Retrieved via AI Analytics 2026-06-24 from https://api.ai-analytics.org/grant/nih/11063903. Licensed CC0.

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