# Pioneering Precision Medicine Approaches for Immune Control of Pediatric HIV-1 Infection

> **NIH NIH P01** · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · 2024 · $149,559

## Abstract

Project Summary/Abstract, Immune Control (Project 4)
Finding a cure for HIV-1 infection is of particular importance for the growing number of HIV-1-infected infants,
children and teenagers who will have to take lifelong antiretroviral therapy if curative treatment options will not
be available. Recent advances suggest that achieving a functional cure of HIV-1 infection may not require
complete elimination of all intact HIV-1 proviruses; instead, it may be sufficient to target intact proviruses
integrated in permissive chromatin positions that support HIV-1 transcription and are more susceptible to viral
reactivation signals. This model for a cure of HIV-1 infection seems to be exemplified by elite controllers, in whom
we documented a highly distinct chromosomal integration site landscape characterized by location of intact
proviruses in heterochromatin regions. Notably, such a “blocked and locked” pattern of proviral integration sites
likely represents the consequence of cellular immune selection forces that have successfully eliminated
proviruses in accessible chromatin locations, while proviruses in heterochromatin positions can persist long term.
This concept raises the possibility that immune-mediated selection mechanisms can be intensified or accelerated
through therapeutic vaccination, and may be preferentially inducible in HIV-1-infected infants starting ART at
early stages of infection. Here, we propose to conduct a detailed analysis of viral reservoir dynamics in infants
undergoing dolutegravir-containing antiretroviral therapy (ART), with the ultimate aim of informing future clinical
trials designed to induce a “blocked and locked” viral reservoir structure through personalized therapeutic mRNA
vaccines incorporating autologous proviral sequences. In specific aim 1, we will investigate viral sequences
near birth and determine the frequency of intact proviruses in infants started on dolutegravir-containing ART,
relative to existing corresponding data from infants undergoing lopinavir/ritonavir-containing ART; these studies
will allow us to track the natural evolution of intact and defective proviruses, and generate an atlas of intact
proviruses that can be considered for inclusion into personalized therapeutic mRNA vaccines to be tested in
future proof-of-principle studies. In specific aim 2, we will longitudinally evaluate the chromosomal positioning
of intact proviruses during continuous ART in these infants; we hypothesize that immune-mediated selection
mechanisms can at least in some infants promote and facilitate a proviral integration site landscape that
approximates the “blocked and locked” proviral architecture observed in elite controllers; such selection
mechanisms may then be further intensified through planned personalized mRNA vaccination in future studies.
In specific aim 3, we will conduct pioneering studies to characterize the quantity and functionality of cellular and
humoral immune responses induced by the licensed SARS...

## Key facts

- **NIH application ID:** 10914864
- **Project number:** 5P01HD107670-04
- **Recipient organization:** HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
- **Principal Investigator:** Mathias Lichterfeld
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $149,559
- **Award type:** 5
- **Project period:** 2021-09-24 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914864

## Citation

> US National Institutes of Health, RePORTER application 10914864, Pioneering Precision Medicine Approaches for Immune Control of Pediatric HIV-1 Infection (5P01HD107670-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10914864. Licensed CC0.

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