# Innate Immune Defects in HIV-Exposed Uninfected Infants: Effect on Respiratory Syncytial Virus Infection

> **NIH NIH K08** · UNIVERSITY OF COLORADO DENVER · 2020 · $162,043

## Abstract

PROJECT SUMMARY/ABSTRACT
 HIV-exposed, uninfected (HEU) infants experience significantly higher rates of morbidity and mortality due
to respiratory syncytial virus (RSV) infection compared to HIV-unexposed (HUU) infants. Natural killer (NK) cells
and antigen-presenting cells (APCs) are innate immune cells that play a critical role in controlling RSV infection.
We have previously identified abnormalities in NK cells and APCs from HEU infants, but it is not clear whether
these abnormalities explain the increased severity of RSV disease observed in this population. This research
seeks to address that knowledge gap and will also investigate which in utero exposures are responsible for
immune dysfunction in HEU infants. This research is relevant to the mission of the NICHD because it will advance
the understanding of immune cross-talk between the pregnant woman and fetus by studying the impact of
maternal HIV infection on neonatal innate immune function.
 The central hypothesis of this proposal is that in utero exposure to the inflammatory environment associated
with maternal HIV infection induces DNA methylation changes in innate immune cells that alter NK cell and APC
function, and ultimately impair the response to RSV infection. This hypothesis will be tested through the following
specific aims: 1) To compare the innate immune response to RSV infection between HEU and HUU infants using
an in vitro model of human respiratory infection; 2) To determine the effect of exposure to an environment
enriched in inflammatory cytokines on neonatal innate immune cell function; 3) To identify differences in DNA
methylation and RNA expression in NK cells and APCs between HEU and HUU infants and determine the effect
of in vitro cytokine exposure on the epigenetic and transcriptomic profile of these cells. Aim 1 will be investigated
using an innovative respiratory epithelial and endothelial co-culture system along with HEU and HUU cord or
peripheral blood mononuclear cells. In Aim 2, HUU NK cells and APCs will be incubated with inflammatory
cytokines to simulate HEU infants’ in utero conditions. Aim 3 will generate the first description of the epigenome
and transcriptome of HEU compared with HUU infants, using robust techniques including DNA methylation
arrays and single cell RNA sequencing.
 This approach is innovative because it: 1) allows the first investigation of the impact of HEU immune
dysregulation on RSV pathogenesis, and 2) may identify the mechanism for immune dysregulation in HEU
infants. This project is significant because it has potential to improve health outcomes for the more than 1 million
HEU infants born each year. Complimentary to the proposed research plan, a five-year mentored career
development training plan has been devised that incorporates didactic learning in genomic data analysis and
hands-on training in virology and immunology laboratory skills. The candidate is co-mentored by internationally
recognized experts in the fields of virolog...

## Key facts

- **NIH application ID:** 9926674
- **Project number:** 1K08HD100205-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Christiana Elizabeth Smith-Anderson
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $162,043
- **Award type:** 1
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926674

## Citation

> US National Institutes of Health, RePORTER application 9926674, Innate Immune Defects in HIV-Exposed Uninfected Infants: Effect on Respiratory Syncytial Virus Infection (1K08HD100205-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9926674. Licensed CC0.

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