# The role of Trained Immunity and Mitochondrial dysfunction on INnate immunity in children and adolescents aGing with PHIV (TIMING-PHIV)

> **NIH NIH U01** · OHIO STATE UNIVERSITY · 2024 · $752,119

## Abstract

Project Summary:
Human immunodeficiency virus (HIV) is associated with persistent immune activation and dysfunction, even
during suppressive antiretroviral therapy (ART) that was initiated early post-infection. Perinatally acquired HIV
(PHIV) infection and lifelong ART likely alter the development and function of the immune system. The
exposure of HIV and ART in utero, the decades of ART therapy, the lasting effects of older toxic ART with
mitochondrial toxicity and the long-term sub-optimal adherence known to occur with prolonged ART use,
heighten concern that sequelae of HIV and ART in children and adolescents may be more frequent and
potentially more devastating than in adults. Better understanding of immune dysfunction in PHIV is crucial, as it
is often easier to limit or even reverse comorbidities at an early stage. We are exploring the consequences of
PHIV and its treatment with ART in a cohort of adolescents in Uganda and have reported significant
differences in the immune profiles of HIV- and HIV+ children. These differences may be driven by trained
immunity, a process by which cells of the innate immune system (e.g. monocytes, macrophages and natural
killer cells) are reprogrammed to respond differently to subsequent exposure to microbial products and
proinflammatory lipids. Recent studies, including our own, demonstrate that ART exposure may also contribute
to alterations in immune cell activation, potentially through decreased mitochondrial function and through
modulation of intracellular signaling cascades. The knowledge gained from this proposal could be substantial,
and from a translational perspective will lay the foundation to identify key pathways with biological, clinical, and
prognostic relevance for adolescents who are advancing into adulthood. These results could inform
intervention trials to mitigate the development of comorbidities associated with immune activation. We propose:
Aim 1: To measure innate immune profiles (i.e monocytes and NK cells) in adolescents with and without HIV in
Uganda and the United States.
Aim 2: To identify the role of trained immunity in innate immune modulation in adolescents with and without
HIV infection in Uganda.
Aim 3: To evaluate how mitochondrial function plays a role in innate immune profiles longitudinally in
adolescents with and without HIV in Uganda.
This proposal combines a well-characterized cohort of children with and without PHIV with ex vivo and in vitro
assessments of immune cell phenotype and function. We will use high-dimensional flow cytometry analyses,
single cell transcriptional profiling, and an in-depth analytical approach to define the potential mechanisms
whereby chronic exposure to ART, microbial products, and clinical and environmental factors may contribute to
innate immune cell activation or dysfunction. This is a continuation of a highly successful collaboration among
the study team members and we are well positioned to perform this innovative project.

## Key facts

- **NIH application ID:** 10789963
- **Project number:** 5U01AI168630-03
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Sahera Dirajlal-Fargo
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $752,119
- **Award type:** 5
- **Project period:** 2022-03-21 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10789963

## Citation

> US National Institutes of Health, RePORTER application 10789963, The role of Trained Immunity and Mitochondrial dysfunction on INnate immunity in children and adolescents aGing with PHIV (TIMING-PHIV) (5U01AI168630-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10789963. Licensed CC0.

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