A groundbreaking study conducted by researchers at UCLA has unveiled a pivotal discovery regarding breast milk composition in women living with HIV. This comprehensive investigation reveals that breast milk from these women exhibits significantly reduced concentrations of tryptophan, a vital essential amino acid intricately linked to infant immune response, physical growth, and neurodevelopmental outcomes. The findings, published in the prestigious journal Nature Communications, provide critical insight into the persistent health vulnerabilities faced by HIV-exposed but uninfected children globally, potentially redefining strategies for maternal and child healthcare in affected populations.
Tryptophan, known for its multifaceted biological roles, serves as a precursor for crucial molecules such as serotonin and melatonin, influencing neurological pathways and immune modulation. The notable depletion of tryptophan discovered in the breast milk of mothers living with HIV suggests a systemic alteration in amino acid metabolism triggered by chronic viral infection and immune activation. Given that approximately 1.3 million children worldwide are born annually to women living with HIV, the metabolic deficiency highlighted by this research may illuminate the underlying causes of increased morbidity and developmental impairments observed in these infants, despite effective prevention of vertical viral transmission.
Historically, children born to mothers with HIV but uninfected themselves have experienced elevated mortality rates and increased susceptibility to infections, growth failure, and cognitive delays, with mortality in low-resource settings reaching up to twice or thrice that of infants born to uninfected mothers prior to the advent of widespread antiretroviral therapy (ART). Intriguingly, even with the implementation of ART, these disparities persist, suggesting that viral suppression alone does not fully mitigate the metabolic disruptions or the inflammatory milieu affecting infant health. Until now, the biochemical and metabolic mechanisms contributing to these outcomes remained poorly understood, underscoring the significance of the present study’s metabolomic approach.
The UCLA team meticulously analyzed a vast repository of breast milk samples collected longitudinally from Zambian women enrolled in a clinical trial that spanned seven years, encompassing both HIV-positive and HIV-negative cohorts. Utilizing state-of-the-art metabolomic profiling techniques, over 800 distinct metabolites were quantified at multiple postpartum intervals, ranging from the neonatal stage through 18 months of lactation. To enhance the robustness of their conclusions, researchers conducted parallel validation in an independent cohort from Haiti, where all HIV-positive participants were undergoing antiretroviral treatment with improved immunologic profiles.
Findings revealed a consistent approximate 50% reduction in tryptophan concentrations in breast milk from HIV-positive mothers compared to controls across all time points. Moreover, an elevated kynurenine-to-tryptophan ratio was observed, a well-established biomarker indicative of heightened immune activation and indoleamine 2,3-dioxygenase (IDO) enzyme activity—a metabolic pathway often upregulated during chronic viral infections and systemic inflammation. These metabolic alterations in the milk were mirrored by decreased plasma tryptophan levels in the mothers, signifying that the depletion is not isolated to the mammary compartment but reflects a broader systemic deficiency possibly mediated by impaired intestinal absorption and sustained immune activation.
In addition to tryptophan metabolism perturbations, the research identified elevated levels of novel antiviral metabolites such as ddhC (3′-deoxy-3′,4′-didehydro-cytidine) alongside increased cytosine and dimethylarginine concentrations in the breast milk of women living with HIV. These molecules are biologically linked to chronic interferon signaling and innate immune responses, further corroborating the presence of persistent viral inflammation despite ART administration. Notably, these profound metabolic fingerprints persisted in the Haitian cohort, affirming their relevance and stability in the context of contemporary HIV therapy and enhanced immune status.
These insights into the altered amino acid metabolism and antiviral metabolite profiles raise compelling questions about the consequences for infant health and development. Tryptophan serves not only as a substrate for protein synthesis but also as a modulator of immune tolerance and neurodevelopmental processes. Deficiencies during critical windows of postnatal growth could underlie the increased incidence of infections, stunted growth, and neurocognitive impairments reported in HIV-exposed uninfected children. The kynurenine pathway metabolites, some of which exhibit neurotoxic properties, may further compound these risks, highlighting the delicate balance between immune activation and metabolic homeostasis in shaping infant outcomes.
Looking forward, the UCLA team stresses caution in translating these findings into clinical practice, emphasizing the complexities of tryptophan metabolism and its downstream pathways. Simple supplementation of tryptophan might inadvertently exacerbate neurotoxic metabolite accumulation if not coupled with interventions targeting the inflammatory cascade and enzymatic dysregulation. Ongoing and future studies will leverage animal models replicating chronic viral inflammation to investigate the safety and efficacy of potential nutritional interventions aimed at restoring metabolic equilibrium, enhancing immune resilience, and promoting optimal cognitive and physiological development in HIV-exposed infants.
Moreover, parallel research endeavors are planned to delineate whether infants born to mothers living with HIV experience systemic tryptophan depletion and altered metabolic processing—a critical extension that may uncover direct metabolic vulnerabilities in this population. Should nutritional or pharmacological strategies prove effective in these investigations, they could revolutionize neonatal care paradigms for the 1.3 million children exposed to HIV annually, reducing disproportionately high rates of morbidity and mortality in regions burdened by the HIV epidemic.
Reflecting on the broader implications, Dr. Grace Aldrovandi, corresponding author and professor at UCLA’s David Geffen School of Medicine, articulates that this study marks a seminal step in understanding the biological underpinnings that link maternal HIV infection to adverse infant health outcomes beyond viral transmission alone. Dr. Aldrovandi highlights that these metabolic insights open novel avenues for therapeutic innovation targeting not the virus per se, but the metabolic and immunologic sequelae that persist despite effective viral suppression. Complementing this perspective, Dr. Nicole Tobin, the study’s lead author, underscores the enduring nature of the metabolic signature, evident despite modern ART, and its explanatory power regarding the continuing disparities faced by these children. Together, these expert interpretations signal a paradigm shift in HIV maternal-child health research, emphasizing metabolic restoration as a frontier for improving long-term outcomes.
In conclusion, this landmark research elucidates a previously unappreciated dimension of HIV pathophysiology—chronic systemic and localized metabolic dysregulation manifesting in lactational biology—and its profound ramifications for infant health. By identifying tryptophan deficiency and heightened immune-metabolic activation in breast milk, the study provides a metabolic explanation for the lingering vulnerabilities of HIV-exposed but uninfected children. Continued interdisciplinary efforts integrating metabolomics, immunology, nutrition, and clinical medicine hold promise for developing targeted interventions that could transform the lives of millions of children born into the context of maternal HIV worldwide.
Subject of Research: People
Article Title: Altered milk tryptophan and tryptophan metabolites in women living with HIV
News Publication Date: 28-Oct-2025
Web References: https://doi.org/10.1038/s41467-025-64566-w
Keywords: Human immunodeficiency virus, Breast feeding
