By Michael Gwarisa
For millions of people living with HIV, achieving an undetectable viral load is the ultimate treatment milestone, a sign that antiretroviral therapy is working and that the virus is under control. But scientists are increasingly discovering that what happens in the blood may not tell the whole story.
New research unveiled during the AIDS 2026 Scientific Highlights press briefing suggests that some adolescents who have successfully suppressed HIV for years still show signs of HIV-specific immune activity in the fluid surrounding the brain and spinal cord, raising new questions about one of the last frontiers in HIV cure research.
The findings come from one of the world’s longest-running studies of children who acquired HIV around the time of birth and began antiretroviral treatment in infancy. Researchers followed 79 South African adolescents who have been on treatment for more than 16 years, making the cohort one of the earliest-treated and longest-followed paediatric HIV populations globally.
Presenting the findings, Shalena Naidoo of Stellenbosch University said the study sought to answer a deceptively simple question: does an undetectable viral load in the blood also mean the central nervous system is completely “quiet” from an immune perspective?
“So when HIV is undetectable in the blood, we generally consider treatment to be working well,” Naidoo said.
“For millions of people living with HIV, viral suppression is the goal of treatment, and it has transformed both life expectancy and quality of life. But we wanted to ask an important question: does an undetectable virus in the blood also mean the brain and the fluid surrounding it are completely quiet from an immune perspective?”
To find out, researchers analysed paired blood samples and cerebrospinal fluid—the clear liquid that surrounds the brain and spinal cord—from adolescents enrolled in South Africa’s landmark Children with Early Antiretroviral Therapy (CHER) study.
The results surprised the researchers.
Among adolescents whose HIV was fully suppressed in their blood, almost one in five still showed evidence of HIV-specific immune activity in their cerebrospinal fluid.
Naidoo stressed that the findings should not alarm people living with HIV.
“I want to be very clear about what this does and does not mean,” she said. “It does not mean that these young people were sick, it does not mean that their treatment was failing, and it does not mean that anyone should change their HIV treatment because of these findings.”
Instead, she said, the research suggests that the immune environment surrounding the brain may not always mirror what doctors observe through routine blood tests.Researchers also found that the blood and cerebrospinal fluid appeared biologically different, despite being connected.
“The blood and the fluid surrounding the brain looked biologically very different,” Naidoo said. “Although they are connected, they do not always tell the same story.”
One of the study’s most promising discoveries was the identification of a distinct protein signature in blood that corresponded with the immune activity detected in the cerebrospinal fluid.
This could eventually help scientists monitor what is happening in the central nervous system without requiring a lumbar puncture, a procedure in which a needle is inserted into the lower back to collect cerebrospinal fluid.
“Our long-term goal is to develop and validate blood-based markers that could one day help identify this type of immune activity without needing invasive sampling,” Naidoo explained.
The study also found that adolescents with persistent HIV-specific immune activity in the cerebrospinal fluid were more likely to have experienced interruptions to antiretroviral treatment over the course of their lives, suggesting that maintaining uninterrupted therapy may be important for long-term immune health within the central nervous system.
The findings are particularly significant as researchers intensify efforts to develop an HIV cure or long-term remission strategies.
Many cure studies involve closely monitoring participants during carefully controlled treatment interruptions to understand whether the virus remains under control without medication.
Naidoo said the new findings suggest that relying solely on blood tests may not provide a complete picture.
“As we move closer to HIV cure and remission, and towards studies in which treatment may be paused or interrupted, we cannot simply assume that silence in the blood means silence everywhere else in the body,” she said.
Although the study identified HIV-specific immune activity in the cerebrospinal fluid, Naidoo cautioned that researchers do not yet know exactly what is driving it.
The laboratory method used in the study detects HIV-specific antibodies but cannot determine whether they represent long-lasting immune memory, antibodies entering the brain from the bloodstream, or ongoing immune activity within the central nervous system.
“What makes our findings very interesting is that the antibody findings were also associated with a distinct immune protein profile in the cerebrospinal fluid,” she said. “We are not interpreting the antibody results in isolation.”
She added that because the study captured participants at a single point in time, longer-term follow-up studies will be needed to determine whether the immune activity reflects persistent immune surveillance, immune memory or ongoing stimulation within the central nervous system.
For now, the research reinforces an important message for scientists searching for an HIV cure: an undetectable viral load remains the cornerstone of successful treatment, but it may not reveal everything happening inside the body.
