South Africa: Study Finds HIV-Specific Immune Activity in Central Nervous System Despite Viral Suppression in Blood

Rio de Janeiro, Brazil — For sixteen years, a group of South African adolescents has been part of one of the world's longest-running HIV studies.

Born with HIV and treated with antiretroviral therapy from infancy, many have spent their entire lives with the virus suppressed to undetectable levels in their blood. Their progress has offered hope that early treatment could protect children from some of the long-term effects of HIV.

But new research suggests the biological picture may be more complex. Researchers wanted to answer a question that routine blood tests cannot: if HIV is controlled in the blood, is it also quiet in the central nervous system?

To find out, they analysed paired blood and cerebrospinal fluid samples from the adolescents.

What they found complicates the picture: even among teens whose HIV was fully suppressed in the blood, nearly one in five still showed signs of detectable, HIV-specific immune activity in their cerebrospinal fluid (CSF), suggesting that HIV-related immune signals may remain detectable in this compartment even when the virus is suppressed in blood. A history of treatment interruption was more common among adolescents with this CSF antibody response.

The findings, presented at AIDS 2026, the 26th International AIDS Conference, suggest that nearly one in five adolescents who had achieved viral suppression in their blood still showed signs of HIV-specific immune activity in their cerebrospinal fluid (CSF), the fluid surrounding the brain and spinal cord. The research analysed adolescents with perinatally acquired HIV who began antiretroviral therapy (ART) during infancy and have been followed for 16 years as part of the PAVE-80 cohort, part of a rare, long-running cohort of children who acquired HIV around birth and began ART during infancy.

"This unique cohort provides a rare opportunity to understand the long-term effects of early treatment," said Shalena Naidoo of Stellenbosch University's Division of Biomedical Sciences in Cape Town, South Africa. "We examined matched blood samples and cerebrospinal fluid from 79 adolescents, and our main finding was both striking and unexpected."

Their findings showed that while 75% of participants had achieved viral suppression in their blood, 11 of the 59 adolescents with suppressed virus - about 19% - still had evidence of detectable HIV-specific immune activity in their cerebrospinal fluid.

"I want to be very clear about what this does and does not mean. 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," Naidoo said. "What it does show is that the immune environment within the central nervous system may not always mirror what we see in the blood."

Naidoo said the researchers found important biological differences between blood and cerebrospinal fluid. This suggests that the two do not always reflect the same immune activity despite being closely connected. She said the team also identified a protein signature in the blood that was associated with what was observed in the cerebrospinal fluid, raising the possibility that, after further validation, blood-based biomarkers might one day help identify this type of CNS immune signal and reduce reliance on lumbar punctures.

"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 such as lumbar punctures," she said.

She said that the findings highlight the need to look beyond blood when assessing HIV persistence, particularly as researchers move closer to HIV cure and remission studies involving treatment interruption. According to Naidoo, the results suggest that viral suppression in blood does not necessarily mean that all HIV-related immune signals are absent from other anatomical compartments in the body, including the central nervous system.

"These young people started treatment in infancy. They have lived with HIV and received treatment for more than 16 years. Their virus is undetectable in the blood, which is the central measure clinicians use to assess whether ART is successfully controlling HIV," said Naidoo. "And yet, in almost one in five, the fluid surrounding the brain still carries the imprint of an HIV-specific immune response. The blood may say HIV is controlled, but beyond the bloodstream, the story may not be over."

What makes the findings particularly interesting?

Naidoo said that the Western blot test used in the study detects HIV-specific antibody binding but cannot determine whether the antibodies reflect long-term immune memory, passive transfer from the blood, or ongoing antibody production within the central nervous system. "Those accompanying immune signatures suggest that the antibody response is associated with a biologically distinct immune state, rather than being an isolated finding," she said.

Naidoo cautioned that the study captured participants at only one point in time.

"Our study was cross-sectional, so we cannot yet determine whether this reflects persistent immune surveillance, immune memory or ongoing antigenic stimulation," she said. "Longitudinal studies, together with measurements of antibody production within the central nervous system and viral persistence, will be needed to answer that question."

Naidoo said that the findings should not alarm participants or their families.

"These young people and their families should not be worried. They are doing well, their viral suppression is real, and nothing in our findings suggests their care should change," she said. "This is a research signal that we're picking up, not a clinical alarm."

Naidoo said the study examined immune activity in the blood and cerebrospinal fluid rather than cognitive or neurological outcomes. While previous research from the Children with HIV Early Antiretroviral Therapy (CHER) cohort has shown that early antiretroviral therapy greatly reduces the risk of HIV-related brain disease, she said researchers are still investigating whether the immune signals observed in cerebrospinal fluid are associated with brain structure, neurological health or cognitive function over time.

She said that earlier neuroimaging studies have found mild but persistent differences in brain structure among people who acquired HIV at birth, and researchers are now working to determine whether persistent HIV-related immune activity could contribute to neuroinflammation or affect cognitive function. However, she cautioned that no causal link has yet been established.

"If this HIV-specific immune activity reflects ongoing inflammatory stimulation within the central nervous system, it could contribute to neuroinflammation over time. Our next step is to determine whether it is associated with markers of neuronal injury, neuroimaging changes or cognitive outcomes," she said.

The research raises a pressing question: could HIV be persisting somewhere the standard blood test can't see?

Researchers say their findings raise important questions about HIV persistence in the brain, but stress that the study does not show the virus is actively replicating there, or that current treatment is failing.

Naidoo said the study found HIV-related immune activity remained detectable in the central nervous system even when participants had achieved long-term viral suppression in their blood.

"Our findings suggest that HIV-related immune activity can remain detectable within the central nervous system even when the virus is suppressed in the blood, but they do not yet prove that actively replicating HIV persists in brain tissue," she said. "We detected HIV-specific antibody responses in cerebrospinal fluid, together with a distinct immune protein profile."

One biologically plausible explanation, she said, is that a small amount of ongoing HIV transcription, antigen production, or low-level viral activity within a central nervous system reservoir continues to stimulate the immune response, even though it is not detectable through routine blood viral-load testing.

However, she cautioned that other explanations. The antibodies could reflect long-lived immune memory, continued antibody production by long-lived plasma cells, local antibody production within the central nervous system, or transfer from the blood.

"What our study shows clearly is that viral suppression in blood does not necessarily mean complete immunological silence within the central nervous system," she said. "To determine whether HIV itself is persisting or replicating there, we now need studies that directly measure viral RNA, viral DNA, viral proteins and replication-competent virus in cerebrospinal fluid and relevant central nervous system cells."

One of the biggest unanswered questions is whether the immune activity has any long-term consequences for brain health.

"The most important unanswered question is whether this immune activity is clinically meaningful over time," Naidoo said. "We need to determine whether it represents protective immune surveillance, a stable immune imprint from earlier infection, or ongoing inflammatory stimulation that could contribute to neuroinflammation and, ultimately, affect brain development or cognitive function."

She said that they also need to know whether the signal persists over time, whether it is linked to ongoing HIV antigen production or low-level viral activity within the central nervous system, and whether adolescents with this immune profile show differences in memory, attention, learning, or other neurocognitive outcomes.

She added that their study was cross-sectional, so it cannot establish whether the immune activity causes harm or predicts future neurological changes.

"The next step is to follow these adolescents longitudinally and relate the cerebrospinal fluid findings to cognitive testing, neuroimaging and biomarkers of neuronal injury and inflammation. That will help us determine whether this is simply a biological footprint of HIV, or a signal with consequences for long-term brain health," she said.

Implications for HIV cure research

The findings also have implications for HIV cure research, suggesting that scientists may need to look beyond the bloodstream when evaluating new therapies.

"Our findings reinforce that HIV cure and remission strategies cannot be evaluated using blood alone," said Naidoo. "The central nervous system is a distinct anatomical and immunological compartment, and a therapy that appears effective in the bloodstream may not have the same penetration or biological effect within the brain and surrounding cerebrospinal fluid."

She added that this is particularly important because the blood-brain barrier can limit the entry of some drugs, while long-lived cells within the central nervous system may harbour HIV or continue producing viral material that sustains an immune response. Cure strategies will therefore need to be designed and assessed with the central nervous system in mind, both to determine whether they reach potential reservoirs and to ensure that they do not trigger local viral activity or harmful inflammation.

She emphasised that the study does not suggest current antiretroviral therapy is failing.

"Our study does not show that current antiretroviral therapy is failing. It shows that viral suppression in blood may not capture all HIV-related biology in other compartments. As cure research advances, success will need to mean more than an undetectable blood viral load; it will require evidence that relevant reservoirs and immune responses throughout the body, including within the central nervous system, have also been adequately addressed," she said.

But our findings do not suggest that current treatment is failing or that routine cerebrospinal fluid testing should become part of standard care.

Blood viral load, she said, remains an essential and highly effective measure of treatment success. "What our study shows is that suppression in blood may not capture all HIV-related immune activity within the central nervous system," she said.

Naidoo said that in the future, monitoring and treatment strategies may need to become more sensitive to what is happening in different anatomical compartments, particularly in people with neurological symptoms and in HIV cure research. She said the long-term goal is to develop blood-based biomarkers that can reliably reflect immune activity in the brain, avoiding the need for repeated lumbar punctures.

For treatment, she added, the key question is whether antiretroviral and future cure-directed therapies adequately reach and act within the central nervous system, while also avoiding harmful inflammation. The broader message is that blood remains indispensable, but it may not always tell the whole story, she said.

For people living with HIV, the message is one of hope, not concern.

For people living with HIV, Naidoo said the findings should be viewed as encouraging rather than alarming. "Antiretroviral therapy has transformed HIV from a fatal disease into a manageable chronic condition, and achieving viral suppression remains one of medicine's greatest successes," she said. Nothing in our study changes that."

But science advances by asking what we have not yet measured, she said. For decades, blood has been the cornerstone of how we monitor HIV because it is accessible and incredibly informative. Our findings remind us that an undetectable viral load in blood, while essential, may not tell the entire biological story.

The central nervous system is one of the body's most protected and complex compartments.

"If we are truly striving for an HIV cure, and not simply viral suppression, we have to understand what is happening there as well. Sometimes the most important discoveries come not from proving what we expected, but from recognising that there is still biology we do not yet fully understand," she said.

She said that she hopes this study encourages us to think beyond what is easiest to measure.

Naidoo said the findings should encourage clinicians and researchers to look beyond the parts of HIV that are easiest to measure. She said the study reinforces that HIV affects the whole body and that understanding what happens in the brain will be essential to improving long-term health outcomes for people living with HIV.

"Our goal is not just to help people survive, but to ensure they can live long, healthy lives with every part of their health, including the brain, in mind," said Naidoo.

South Africa: Study Finds HIV-Specific Immune Activity in Central Nervous System Despite Viral Suppression in Blood

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