Gene Therapy Offers Lifelong HIV Protection in Newborns

Groundbreaking Study Targets Critical Early-Life Immune Window

A revolutionary gene therapy delivered via a single injection at birth shows promise for years-long protection against HIV. This pioneering approach leverages a crucial early-life period when the immune system is naturally more receptive, potentially transforming the fight against pediatric infections in vulnerable regions.

Harnessing Early Tolerance for Lasting Immunity

Research published in *Nature* indicates that the initial weeks of life, characterized by heightened immune tolerance, represent an optimal window for gene therapy administration. Treatments that might be rejected by a more developed immune system in older individuals could be successfully integrated if given shortly after birth. This breakthrough could significantly impact newborn protection in areas with high HIV risk.

Dr. **Amir Ardeshir**, an associate professor at the Tulane National Primate Research Center and lead author, highlighted the urgent need for such interventions. “Nearly 300 children are infected with HIV each day,” he stated. “This approach could help protect newborns in high-risk areas during the most vulnerable period of their lives.”

“This is a one-and-done treatment that fits the critical time when these mothers with HIV in resource-limited areas are most likely to see a doctor. As long as the treatment is delivered close to birth, the baby’s immune system will accept it and believe it’s part of itself.”

—Amir Ardeshir, Associate Professor of Microbiology and Immunology, Tulane National Primate Research Center

The study involved nonhuman primates receiving a gene therapy designed to equip cells with the ability to continuously produce antibodies that combat HIV. The timing of this single-dose treatment was paramount for its long-term efficacy. Animals treated within their first month of life remained protected for at least three years without requiring booster shots, suggesting potential lifelong coverage for humans.

A New Arsenal Against Mother-to-Child Transmission

In contrast, primates treated between 8 and 12 weeks of age demonstrated a less effective immune acceptance of the therapy due to their more developed and less tolerant immune systems. This finding underscores the critical importance of administering the treatment during the neonatal period.

Annually, over 100,000 children contract HIV, with mother-to-child transmission post-birth, often through breastfeeding, being the primary route. While antiretroviral therapies have been effective in managing the virus and preventing transmission, consistent adherence and medical access often wane after childbirth, particularly in areas with limited healthcare infrastructure.

To deliver the gene therapy, researchers utilized an adeno-associated virus (AAV) vector. This harmless virus serves as a delivery vehicle for genetic material, directing muscle cells—chosen for their longevity—to continuously produce broadly neutralizing antibodies (bNAbs). These bNAbs are crucial for combating a wide array of HIV strains.

This method addresses a significant hurdle in bNAb research: previous attempts required frequent, costly infusions, presenting substantial logistical challenges in low-resource settings. “Instead, we turn these muscle cells – which are long-lived – into micro factories that just keep producing these antibodies,” explained **Ardeshir**.

Newborn recipients exhibited greater tolerance and sustained high levels of bNAbs, successfully preventing infection during simulated breastfeeding exposures and later scenarios mimicking sexual transmission. Older infants and juveniles were more prone to developing anti-drug antibodies that neutralized the treatment’s effectiveness.

Furthermore, exposing fetuses to the antibodies prenatally appeared to enhance older infants’ acceptance of the gene therapy later in life, circumventing the immune rejection often associated with aging.

**Ardeshir** noted that a single injection at birth presents a more cost-effective and practical real-world solution, minimizing the burden on mothers for follow-up appointments.

Future Implications and Challenges Ahead

While these results are highly promising, further research is needed to confirm their translation to human infants and children, who might respond differently to AAV-delivered therapies. The study also utilized a single strain of simian–human immunodeficiency virus, and the variability of human HIV strains will need consideration.

If proven effective in humans, this therapy could drastically reduce mother-to-child HIV transmission rates, especially in sub-Saharan Africa, where approximately 90% of pediatric HIV cases originate. The approach may also be adaptable for protecting against other diseases, such as malaria, which disproportionately affects young children in low-income countries.

“Nothing like this was possible to achieve even 10 years ago,” stated **Ardeshir**. “This was a huge result, and now we have all the ingredients to take on HIV.”

This groundbreaking research received support from the National Institutes of Health through base grants to the Tulane National Primate Research Center (P51OD011104) and the California National Primate Research Center (P51OD011107).