Transient rapamycin treatment enables long-term delivery of anti-HIV antibodies

The fight against HIV has seen remarkable advances, particularly with the development of broadly neutralizing antibodies (bnAbs) that can target diverse strains of the virus. However, delivering these antibodies efficiently and sustainably remains a challenge.

A Nature Communications study led by Ronald Desrosiers, Ph.D., professor of pathology and laboratory medicine and vice chair of basic research at the University of Miami Miller School of Medicine, introduces a promising solution. The research team looked at transient treatment with the immunomodulatory drug rapamycin to enable long-term delivery of anti-HIV bnAbs via adeno-associated virus (AAV) vectors.

Finding a Better Gene Therapy

AAV-mediated gene therapy offers a one-time administration route for lifelong antibody production. The approach circumvents the need for repeated infusions and improves the likelihood that patients will adhere to treatment.

Despite its promise, the approach has been hampered by host immune responses, particularly the development of anti-drug antibodies (ADAs) that neutralize the delivered bnAbs and limit their therapeutic effect. Previous attempts to reduce immunogenicity, such as vector engineering and antigen tolerization, have yielded only partial success.

The study aimed to determine whether transient rapamycin treatment could prevent ADA formation and allow continuous, long-term delivery of anti-HIV bnAbs in animal models. Researchers chose rapamycin, an FDA-approved immunosuppressant commonly used in transplantation, for its ability to modulate immune responses without long-term toxicity.

Study Methodology

The research was conducted in two phases:

• Phase 1: Ten mice with functioning immune systems were divided into two groups: five received rapamycin and five served as controls.

Rapamycin was administered intraperitoneally three times a week, starting one week before AAV injection and continuing for 11 weeks. All mice received AAV9 encoding the immunogenic bnAb C-rh 3BNC117. Plasma levels of bnAbs and ADAs were measured over 28 weeks.

• Phase 2: Five rhesus macaques received daily rapamycin injections starting two weeks before AAV administration, then three times weekly for 12 weeks. Each monkey was injected with three AAV9 vectors encoding different bnAbs: C-rh 3BNC117, C-rh 10-1074, and C-rh PGT145. Serum bnAb levels and ADA responses were monitored for more than a year.

Key Findings: No Detectable ADAs

Rapamycin-treated mice showed no detectable ADAs during and after treatment. Control mice, conversely, developed robust ADA responses. The treated group maintained significantly higher plasma levels of bnAbs, indicating successful long-term delivery.

In the monkeys, 12 of 15 bnAb delivery attempts were successful, with sustained therapeutic antibody levels and minimal ADA formation. Notably, ADA responses emerged only in animals with subtherapeutic rapamycin levels, underscoring the importance of proper dosing.

Why is this Research Important? 

This research marks a significant step toward making AAV-mediated antibody gene therapy viable for HIV prevention and treatment. By avoiding unwanted immune responses, transient rapamycin treatment could enable consistent, long-term delivery of therapeutic antibodies from a single administration. This approach has the potential to:

• Reduce the burden of repeated infusions and improve patient adherence
• Reduce health care costs by minimizing the need for ongoing antibody production
• Enhance the durability and effectiveness of HIV prophylaxis and therapy, especially in resource-limited settings

Transient rapamycin treatment offers evidence and hope for durable, cost-effective HIV prevention and treatment, a gratifying finding for Dr. Desrosiers.

“I have made a number of important scientific contributions in my career, including the initial discovery of SIV, the close monkey relative of HIV,” he said. “But these contributions have all been at a basic, fundamental level. This is the first time in my career that I have contributed something that is directly applicable to human use.”