N-803 & HIV Cure Research: CROI 2026 Updates on Viral Rebound & Immune Response

The search for a functional cure for HIV – long-term remission without the need for daily antiretroviral therapy – continues to face challenges, with recent research indicating that the immune-modulating drug N-803 (also known as Anktiva) doesn’t consistently deliver the hoped-for delay in viral rebound after stopping treatment. While earlier findings sparked optimism, a more comprehensive picture emerging from several clinical trials presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2026) suggests a combination approach will likely be necessary to achieve sustained control of the virus.

Understanding the HIV Reservoir and the Quest for a Cure

Antiretroviral therapy (ART) is remarkably effective at suppressing HIV to undetectable levels in the blood. However, the virus isn’t eradicated. It establishes a persistent “reservoir” of infected cells, primarily CD4 T cells, where the virus lies dormant. This reservoir represents a major obstacle to a cure given that if ART is stopped, the virus can reactivate from these cells, leading to “viral rebound.” Researchers are exploring various strategies to shrink this reservoir and bolster the immune system’s ability to control the virus, but progress has been incremental. A glossary of terms related to HIV research can be found on aidsmap.com.

N-803: From Cancer Treatment to HIV Research

N-803, developed by ImmunityBio, is an interleukin 15 (IL-15) receptor ‘superagonist.’ Essentially, it’s designed to stimulate the immune system, specifically activating natural killer (NK) cells and CD8 killer T cells, while also enhancing the activity of CD4 helper T cells and promoting the proliferation of memory T cells. The US Food and Drug Administration approved N-803 in 2024 for treating bladder cancer, and Saudi Arabia recently approved it for advanced lung cancer. Its potential to also awaken the immune system to fight HIV, and potentially reactivate the latent virus within the reservoir, led to its investigation as a potential component of a functional cure strategy.

Initial Promise and Subsequent Trials

Early results from a study sponsored by Rockefeller University, presented at the International AIDS Society Conference on HIV Science (IAS 2025), showed encouraging signs. Participants received broadly neutralizing antibodies (bnAbs) – lab-created antibodies that target a wide range of HIV strains – followed by N-803 injections. A significant proportion remained off ART for extended periods, even up to a year in some cases. Broadly neutralizing antibodies are designed to defend cells from HIV, and some are being studied in clinical trials.

However, findings from two larger trials – ACTG A5386 and RV550 – presented at CROI 2026, painted a more nuanced picture. ACTG A5386, sponsored by the US National Institutes of Allergy and Infectious Diseases, involved 48 participants. While N-803 appeared safe and well-tolerated (though some participants experienced temporary white blood cell deficiencies), it didn’t lead to sustained viral control after participants stopped ART. Only one participant (5%) maintained a viral load below 200 copies at eight weeks off ART. The RV550 trial, conducted in Thailand, also found that N-803, even when combined with ART, didn’t significantly alter the time to viral rebound after treatment interruption.

Immune Responses and the Viral Reservoir: A Glimmer of Hope

Despite the lack of consistent viral control, researchers observed some positive changes in immune responses. Analysis of data from ACTG A5386 showed that N-803 was associated with a transient decline in intact HIV DNA – a measure of the viral reservoir – in some participants. Those who received N-803, with or without bnAbs, showed shifts towards “stem-like” T cells, which have a greater capacity to proliferate and fight HIV. These findings suggest that N-803 may be modulating the immune system in ways that could be beneficial, even if it doesn’t achieve sustained viral suppression on its own. The study also showed increased activity of CD8 T cells specific to HIV proteins.

What Does This Mean for the Future of HIV Cure Research?

The recent findings underscore the complexity of achieving a functional cure for HIV. The initial excitement surrounding N-803 has tempered, but the research isn’t a dead finish. The data strongly suggest that a single agent, even one that effectively stimulates the immune system, is unlikely to be sufficient. Combination strategies, incorporating multiple approaches to both shrink the reservoir and enhance immune control, are now seen as the most promising path forward.

Researchers are now exploring other avenues, including bispecific antibody-like constructs that deliver IL-15 directly to memory CD4 cells. These constructs, developed by Dr. David Ho’s lab, have shown a remarkable ability to activate latent HIV in laboratory settings.

Next Steps in HIV Cure Research

The field is rapidly evolving, and several key areas of investigation are underway. Ongoing clinical trials are evaluating different combinations of immunotherapies, latency-reversing agents, and broadly neutralizing antibodies. Researchers are also focusing on identifying biomarkers that can predict which individuals are most likely to respond to specific treatment strategies. Further research is needed to understand the factors that contribute to viral control in the few individuals who have achieved long-term remission off ART, and to translate those insights into effective therapies for a wider population. The pursuit of an HIV cure remains a challenging but vital endeavor.