Tryptophan deficiency in breast milk may explain health challenges in children born to mothers with HIV

A new UCLA study reveals that breast milk from women living with HIV contains significantly lower levels of tryptophan, an essential amino acid likely important for infant immune function, growth, and brain development. This discovery may help explain why children born to women living with HIV experience higher rates of illness and developmental challenges, even when the children themselves are not infected with the virus. The study appears in Nature Communications.

Why it matters

Approximately 1.3 million children are born to women living with HIV annually worldwide. Even with effective antiretroviral therapy that prevents HIV transmission, these children who are exposed to HIV but not infected continue to face a 50% increase in mortality in low-income settings along with increased risks of infections, growth problems, and cognitive challenges. Prior to antiretroviral therapy, these children had mortality rates that were two to three times higher than infants not exposed to HIV. Understanding why these children remain vulnerable despite not being infected has been a critical gap in maternal and child health research. This study provides the first metabolic explanation for these persistent health disparities and points toward potential nutritional interventions that could protect vulnerable infants.

What the study did

Researchers analyzed 1,426 breast milk samples collected over 18 months from 326 women in Zambia, 288 living with HIV and 38 without HIV, as part of a clinical trial conducted between 2001 and 2008. Using advanced metabolomics technology, the team measured over 800 different metabolites in the milk samples collected at multiple timepoints, from one week postpartum through 18 months. They then validated their findings in a second cohort of 47 women from Haiti who were receiving antiretroviral therapy. Additionally, researchers performed targeted quantitative analysis of tryptophan and kynurenine levels in both breast milk and blood plasma to understand whether the depletion was localized to milk or reflected systemic changes in the mothers' bodies.

What they found

Breast milk from women living with HIV contained significantly lower tryptophan levels throughout the entire 18-month study period, with concentrations approximately 50% lower than in milk from women without HIV. The kynurenine-to-tryptophan ratio, a marker of immune activation, was significantly elevated at all study visits. Plasma measurements also found lower tryptophan levels in women in mothers living with HIV, suggesting that the decreased level of tryptophan in milk stems from systemic depletion likely secondary to reduced intestinal absorption rather than impaired transfer to milk. The research team also identified elevated levels of a newly discovered antiviral compound called ddhC in the milk of women living with HIV, along with increased cytosine and dimethylarginine, all markers consistent with chronic viral inflammation and interferon activation. These metabolic alterations persisted even in the validation cohort of women on antiretroviral therapy with higher immune function, indicating the pattern remains relevant in modern treatment settings.

What's next

Researchers emphasize that these findings require careful follow-up before any nutritional interventions can be recommended. The team plans to investigate whether tryptophan supplementation in animal models of chronic viral inflammation can safely improve immune function, growth, and cognitive development without unintended consequences. Since the inflammatory environment in HIV infection drives tryptophan down pathways that can produce neurotoxic metabolites, simply replacing tryptophan without modulating these pathways could potentially cause harm. Future studies will also explore whether infants of mothers living with HIV have reduced systemic tryptophan levels and alterations in the way their bodies process tryptophan. If safe and effective interventions are identified, they could benefit the 1.3 million children born annually to women living with HIV worldwide.

From the experts

We've known for years that children born to mothers living with HIV face greater health challenges, but we didn't fully understand why. This study reveals that tryptophan deficiency and altered metabolism may serve as a common denominator explaining the immune, growth, and cognitive differences we see in these children."

Dr. Grace Aldrovandi, corresponding author of the study and professor of Pediatrics and chief of the Division of Infectious Diseases at UCLA's David Geffen School of Medicine

"What's particularly striking is that this metabolic signature persists even when mothers are on effective antiretroviral therapy," added Dr. Nicole Tobin, professor of pediatrics at the UCLA David Geffen School of Medicine and the study's lead author. "That helps explain why these children continue to need extra support despite advances in HIV treatment."