# The effect of HIV exposure and infection on immunity to TB in children

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $793,352

## Abstract

Project Summary / Abstract
Over one million new cases of tuberculosis (TB) and 239,000 TB-related deaths occur in children each year.
Despite evidence that HIV exposure in children is associated with a markedly increased risk of infection with
Mycobacterium tuberculosis (Mtb) and development of TB disease, few studies have explored mechanisms for
HIV-related susceptibility to TB in children. HIV-exposed uninfected children (HEU) are exposed in utero to
both maternal HIV and anti-retroviral therapy (ART) and these exposures may influence subsequent immune
responses to Mtb. In settings with high prevalence of HIV and TB, newborns typically receive BCG vaccination
within the first few days of life, which confers some protection against severe forms of TB in young children.
Interestingly, BCG vaccination has also been recognized to confer non-specific beneficial effects, including
reduced neonatal and infant mortality. Moreover, vaccination with BCG is associated with enhanced innate
immune responses to mycobacteria as well as heterologous pathogens, a phenomenon termed “trained
immunity”. Epigenetic reprogramming of innate immune cells, including monocytes and NK cells, is one
mechanism identified that contributes to BCG-induced trained immunity. The effect of maternal HIV exposure
and infant HIV infection on induction of trained immunity to Mtb in BCG-vaccinated infants has not been
described. Our studies will characterize innate and adaptive immune responses to mycobacteria, cofactors
such as ART that may influence immune responses, and the implications of these immune responses for
susceptibility to pediatric Mtb infection. We will test the hypotheses that (1) maternal HIV exposure and infant
HIV infection dampen induction of trained immunity to Mtb via epigenetic reprogramming of innate immune
cells in BCG-vaccinated infants; and (2) ART enhances innate and adaptive anti-mycobacterial immune
responses in HIV-infected children and that deficits in anti-mycobacterial immunity will predict acquisition of
Mtb infection. Using clinically-well characterized longitudinal cohorts of infants and children in Kenya, we will
perform a comprehensive analysis of the phenotype, function, epigenome and transcriptome of innate immune
responses in HEU, HIV-infected, and HIV-unexposed uninfected infants. We will then determine the capacity of
ART to restore innate and adaptive anti-mycobacterial immune responses in HIV-infected children and identify
immune correlates that predict acquisition of Mtb infection. These studies will provide unprecedented insights
into mechanisms of HIV-associated modulation of immunity to Mtb in infants and children and will inform novel
TB preventive interventions in these at-risk populations.

## Key facts

- **NIH application ID:** 9843446
- **Project number:** 5R01AI142647-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Cheryl Liane Day
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $793,352
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843446

## Citation

> US National Institutes of Health, RePORTER application 9843446, The effect of HIV exposure and infection on immunity to TB in children (5R01AI142647-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9843446. Licensed CC0.

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