# Neonatal Immunity to novel TF SHIVs

> **NIH NIH R37** · DUKE UNIVERSITY · 2024 · $824,062

## Abstract

Infants and children living with HIV-1 develop HIV-1 envelope (Env)-reactive broadly neutralizing antibodies
(bnAbs) with a higher frequency and faster kinetics than adults, but the mechanisms of pediatric bnAb
induction are not fully defined. Importantly, understanding the cellular and molecular mechanisms of bnAb
induction in pediatric subjects will improve our understanding of pediatric HIV-1 immunity, and inform pediatric
HIV-1 vaccine design to elicit bnAbs. We recently used a chimeric simian-human immunodeficiency virus
(SHIV) to infect neonate RMs that generated heterologous HIV-1 nAbs over time as young RMs. Following
neonatal SHIV infection in rhesus macaques (RMs), 8/13 (62%) animals generated plasma nAbs against
heterologous HIV-1, with increased titers over time (6-24 months) in association with enhanced germinal
center (GC) activity, including antigen (Ag)-specific GC B cells—a known mechanism for bnAb induction in
humans. After neonatal rearing, the available dams were infected with the same SHIV and 3/11 (27%) dams
generated heterologous HIV-1 nAbs with increased titers over time. Compared to neonate RMs, dams also had
lower mean plasma viral load over time, and higher levels of CD4 T follicular regulatory cells (Tfr)—both of
these mechanistic differences are known to impact bnAb development. Thus, we now have an appropriate
model to define pediatric HIV-1 immunity associated with Env-reactive bnAb induction. In this proposal, we will
define the unique specificities of pediatric immunity associated with HIV-1 bnAb induction using immune cell
transcriptomics (Aim 1) combined with viral env evolution analyses (Aim 2) in young SHIV-infected RMs. In
Aim 3, we will isolate and characterize blood and GC B cell-derived HIV-1 nAbs in young RMs following
neonatal SHIV infection, with a focus on defining the maturation of pediatric nAbs that can develop into bnAb
status. Finally, we will use env-nAb coevolutionary analyses to identify candidate Env immunogens to elicit
HIV-1 bnAbs as previously described. The specific aims for this proposal are as follows:
Aim 1. To define the permissive immunologic milieu for heterologous HIV-1 nAb induction in pediatric
subjects.
Aim 2. To identify env mutation patterns associated with neutralization breadth development following
 SHIV-infection in young and adult RMs.
Aim 3. To define the characteristics and maturation pathways of heterologous HIV-1 nAbs elicited
 following neonatal SHIV infection.

## Key facts

- **NIH application ID:** 10918706
- **Project number:** 2R37AI140897-06A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Wilton B Williams
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $824,062
- **Award type:** 2
- **Project period:** 2018-08-15 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10918706

## Citation

> US National Institutes of Health, RePORTER application 10918706, Neonatal Immunity to novel TF SHIVs (2R37AI140897-06A1). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10918706. Licensed CC0.

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