Results from the RIO clinical trial reveal that administering broadly neutralizing antibodies to adults living with HIV can suppress the virus for months or years after stopping daily antiretroviral medication. Researchers found that patients’ natural immune responses work alongside the antibodies, while the treatment accelerates the decline of the latent viral reservoir.
Standard medical management for human immunodeficiency virus relies heavily on daily antiretroviral therapy, a proven approach that transforms a once-fatal diagnosis into a manageable chronic condition. Yet, this daily regimen is not a cure. Antiretroviral drugs cannot clear out the dormant virus residing in long-lived immune cells, a stubborn viral reservoir that remains latent for decades and immediately restarts active infection if daily treatment stops.
Now, data published in Nature Medicine from the multi-site RIO trial offer a different path forward. Led by researchers at The Rockefeller University, Imperial College London, and the University of Oxford, the trial tested whether long-acting broadly neutralizing antibodies could control the virus independently after a carefully supervised pause in daily medication.
Trial Design and Participant Requirements in the RIO Study
The RIO study operated as a randomized, placebo-controlled, double-blinded phase 2 trial across multiple clinical research sites in the United Kingdom and a single site in Denmark. Oversight for the clinical protocol involved multiple regulatory bodies, including the London–Westminster Research Ethics Committee, the UK Health Research Authority, the UK Medicines and Healthcare products Regulatory Agency, and the Danish Medicines Agency.
To qualify for enrollment, participants had to meet rigorous clinical criteria. The trial enrolled individuals aged 18 to 60 who initiated antiretroviral therapy during confirmed primary HIV infection or early-stage infection and maintained virological suppression for at least one year. Eligible participants demonstrated adequate hemoglobin levels, a body weight of at least 50 kg, screened negative for active hepatitis B and C, and received a SARS-CoV-2 vaccination at least four weeks prior to enrollment.
Antibody Infusions and Long-Term Viral Suppression
The trial randomized 68 men living with HIV to receive either two long-acting broadly neutralizing antibodies or a placebo before pausing their daily antiretroviral therapy. Initial findings indicated that a single antibody dose allowed most participants to keep HIV at undetectable levels for up to 20 weeks without daily medication.
Individuals who maintained viral suppression were offered a second dose of the broadly neutralizing antibodies at the 20-week mark. Half of those participants remained undetectable at 48 weeks, and one-third maintained suppression out to 72 weeks.
“The antibodies appear to be teaching the immune system to control HIV,” says Michel C. Nussenzweig, head of the Laboratory of Molecular Immunology. “It’s almost as if the participants’ own immune activity acts as a second component to the antibodies. Together, the bNAbs and the natural immune response seem to work together to corner the virus.”
Distinctive Patterns of Immune Control and Circulating Antibodies
Beyond complete suppression, researchers observed another sign of viral control among participants who eventually developed detectable virus after receiving the antibodies. Specifically, 38 percent of the 29 participants who received broadly neutralizing antibodies and later showed detectable virus developed a distinctive pattern of fluctuating viremia. In these cases, HIV repeatedly rose and fell at low levels without ever crossing the threshold required to restart standard antiretroviral therapy, persisting for up to 58 weeks.
This sustained management occurred even after the administered antibodies completely cleared the body. Laboratory analysis showed that participants who already carried their own neutralizing antibodies against HIV managed the infection more effectively, implying that natural immunity and administered antibodies operate in tandem.
Laboratory Analysis of the Latent Viral Reservoir
To uncover why certain participants controlled the virus for extended periods, researchers examined blood samples collected throughout the trial. Genetic assays separated intact, potentially infectious HIV from defective copies, allowing the team to trace how rebounding viruses interacted with both treatments and natural antibodies.
The investigation revealed that rebounding viral strains rarely matched the dominant intact proviruses circulating in the blood, indicating they likely stemmed from unsampled tissues or deeply dormant viral pools. Furthermore, while the initial size of the latent reservoir did not predict how long a participant stayed off daily medication, intact proviruses declined with an estimated half-life of just 36 weeks following broadly neutralizing antibody therapy—a significant acceleration compared to the four-to-seven-year half-life observed during standard antiretroviral treatment.