Investigating mechanistic pathways of neurodevelopmental impairment in HIV-exposed, uninfected infants (IHEU)

The National Institute of Child Health and Human Development (NICHD) awarded Rutgers The State University of New Jersey, Robert Wood Johnson Health Sciences School of Nursing, $3.297 million in federal research funding on August 1, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865).

The research investigates mechanistic pathways linking gut microbiota alterations to neurodevelopmental impairment in HIV-exposed, uninfected infants (IHEU). The project evaluates associations between the enteric bacteriome or virome during the first six months of life and neurodevelopmental delay at 24 months of age in IHEU, and identifies the most influential postnatal developmental window. The recipient will investigate relationships between the plasma metabolome in IHEU and subsequent neurodevelopmental delay risk. To assess causation, the project includes fecal material transplant or fecal filtrate transplant from IHEU with or without neurodevelopmental delay into neonatal germ-free mice, with assessment of brain structure via magnetic resonance imaging, neurogenesis at weaning, and behavioral evaluation.

Performance of work occurs at Newark, New Jersey. The award period runs through July 31, 2029.

Abstract

With expanded access to combination antiretroviral therapy (CART), there has been a decline in vertical transmission of HIV. This success has led to a growing population of infants who are HIV-exposed but uninfected (IHEU). Despite maternal CART and breastfeeding, IHEU display a higher risk for neurodevelopmental delay (NDD) compared to infants who are HIV-unexposed, uninfected (IHUU). Prior studies have reported reduced subcortical brain volume in IHEU, which are associated with greater odds of cognitive, language and receptive delay. However, the mechanisms underlying this elevated risk remain poorly understood. Emerging evidence implicates the GUT microbiota and its metabolic products in shaping brain development and behavior. In prior work, we observed distinct alterations in the GUT microbiota of IHEU compared to IHUU at 4- weeks of age. Yet, whether these early life GUT microbiota alterations contribute to elevated risk of NDD in IHEU remains untested. Furthermore, whether a causal relationship exists between early GUT microbiota of IHEU and later neurodevelopmental outcomes is unknown. While the GUT microbiota encompasses both bacterial and viral communities (VIROME), the contribution of IHEU VIROME to neurodevelopment is unexplored. To address these gaps, I will evaluate associations between the enteric bacteriome or VIROME during the first 6 months of life and NDD at 24 months of age in IHEU and identify the most influential postnatal window (goal 1). Additionally, I will investigate the relationship between the plasma metabolome in IHEU and subsequent NDD risk (goal 2). To assess causation, I will perform fecal material transplant or fecal filtrate transplant from IHEU with or without NDD into neonatal germ-free mice. I will assess brain structure (via magnetic resonance imaging) and neurogenesis at weaning and evaluate behavior at both weaning and adolescence. Additionally, I will explore the neuroprotective effect of specific metabolites predictive of NDD, and assess whether bacterial taxa associated with favorable neurodevelopmental outcomes in IHEU exert direct effects on brain developments and behavior (goal 3). This project aims to identify microbial and metabolic drivers of poor neurodevelopment in IHEU and inform early-life interventions, including the potential development of probiotic therapies or microbial- derived metabolites that could serve as novel therapeutic agents to protect against neurodevelopmental impairments. Findings may also have broader implications to infants globally and in the USA who experience microbiota disruptions, such as from early-life antibiotic exposure.