In some cases, HIV can bypass the barrier that encases the brain and cerebrospinal fluid which can contribute to brain inflammation and neurocognitive symptoms. However, diagnosing this viral ‘escape’ into cerebrospinal fluid is challenging due to its anatomical inaccessibility. Swiss researchers found that the presence of the virus did not clearly correlate with symptoms. In their paper published in the Journal of Acquired Immunodeficiency Syndromes, they also conclude that the only way to know whether the virus is present in the cerebrospinal fluid is taking a small amount of fluid directly from the spine.
The brain with the spinal cord and the surrounding fluid are separated from the rest of the body by the so-called blood-brain barrier; one of its major functions is to protect the fragile nervous system from infections that may take place elsewhere in the body. The surrounding fluid is called cerebrospinal fluid (CSF), and its content may change depending on the health of the brain and the integrity of the blood-brain barrier. In some people with HIV, the virus may make its way into the cerebrospinal fluid or the brain, even when the virus is undetectable in their blood.
Several factors can affect whether HIV will reach the brain and whether that will lead to neurocognitive deficits. Some of these are the neurovirulence (its attraction to nerve cells) of the strain of the virus a person has; the health of the barrier that encases the brain, the spinal cord and its fluid; the state of the immune system and the presence of other infections. However, whether the presence of the virus in the cerebrospinal fluid in otherwise virally suppressed people directly leads to symptoms and deficits is debated and may vary from person to person. Besides, there are many cases where the virus is not detected but symptoms and deficits persist.
Scientists rely on detecting HIV in CSF as a definitive proof for viral ‘escape’ into the central nervous system (brain and spinal cord). However, this is an invasive technique known as lumbar puncture or spinal tap. It involves taking a sample from the CSF using a syringe that penetrates the lower spine and comes with risks such as headache and short-term numbness in legs. Rarely, it can lead to serious infections. Lumbar puncture can also be used to look at certain inflammatory proteins to help decide whether there is brain inflammation. The present study looks at a large set of data from people who underwent lumbar puncture; the authors failed to find a definitive link between viral presence in CSF and symptoms and established that the clinical features of those with and without viral escape were similar.
The investigators collected their data from two Swiss cohorts of people living with HIV focused on neurocognitive and metabolic health. They focused on 288 participants who had neurocognitive symptoms and had undergone lumbar puncture between 2011 and 2019.
As well as testing the CSF for HIV RNA, the researchers also looked at other features of CSF such as white blood cell count, CD4 count and protein levels to get an approximate idea of the inflammatory state of the central nervous system. In order to really be comprehensive, they even ran resistance tests on the virus when detected in CSF, looked at the drug combinations of participants in relation to their ability to reach the CSF and finally did a brain scan (MRI) to look for structural changes in the brain.
Viral escape in 25 participants
Viral escape in CSF was defined either as any detectable virus in CSF in otherwise undetectable people on treatment, or CSF viral load greater than blood viral load in those who were not virally suppressed. It was found in 25 of the 288 participants, including 19 who were otherwise virally suppressed (undetectable) at the time they had viral escape in CSF.
Interestingly, there was no distinction between those with and without viral escape in terms of other parameters such as time since diagnosis, CD4 count, neurocognitive scores, other health conditions and effectiveness of their regimen in reaching the CSF. In other words, there was nothing predictive of the viral escape.
Similar MRI findings in those with and without viral escape
The investigators did brain scans (MRI) to look for structural changes in the brain. Subtle to moderate brain changes were observed across both groups (those with and without viral escape) with involvement of different brain regions. Nearly 70% of participants in each group were found to have some kind of structural change in their brain.
Similar rates of neurocognitive changes
The presence of neurocognitive symptoms was based either on self-reported complaints or those observed by a clinician. Neurocognitive impairment (NCI), on the other hand, was assessed through neurocognitive tests.
Both, those with and without viral escape had similar rates of non-symptomatic neurocognitive impairment (around 40% in each group) and mild neurocognitive impairment (less than 5%). It was interesting, but not significant, to observe one participant with HIV-associated dementia in the group without viral escape, while there were none in the viral escape group.
CSF resistance in three participants
The virus analysed from three of the participants with detectable CSF viral load was resistant to the treatment they were taking at the time of the measurement, while the virus in their blood had no resistance. This highlights the isolated nature of the central nervous system and that some virological events may take place independently in that anatomical site.
Is lumbar puncture justifiable?
Our understanding of the neurocognitive involvement and changes that accompany well-treated HIV infection is still in its infancy. Nevertheless, this study makes a major stride by showing that there were no clinical differences between those with and without viral CSF escape; hence, there was nothing predictive. The only definitive method is lumbar puncture, however, is it justifiable? In the context of effective HIV treatment, neurocognitive impairment seems to be a function of many factors where CSF escape is only one of them. In that case, do lumbar puncture analyses contribute to an improvement in patient outcomes and quality of life?
Many experts believe that a lumbar puncture may at least guide the healthcare practitioner into choosing a drug combination that is better at reaching the CSF; yet there are scarce data that shows treatment optimisation (or intensification) helps with neurocognitive symptoms in already undetectable people with proven viral escape. Contrary to expectations, most data so far seems to render that approach unnecessary or minimally effective; in some cases, increasing the drug burden may worsen those symptoms due to the drugs’ own side effects.
Given the rather unconvincing correlation between viral escape and neurocognitive symptoms and deficits in undetectable people under treatment, proving viral escape may not be useful in routine clinical care. There is a complex interaction between the virus, the immune system, and the local immunity of the central nervous system. The evidence so far seems to point towards this interaction rather than solely the presence of the virus in CSF as determining whether symptoms and deficits will manifest.
However, one thing is certain – people with HIV face higher rates of neuro-psychological and neurocognitive impairment and all possible avenues for intervention must be explored to improve quality of life. One area of possibility, that so far has been underexplored, is immune interventions for the central nervous system. Instead of focusing on the virus directly, when already undetectable, immune responses could be improved through various brain-targeted anti-inflammatories or other drugs so that the immunological environment of the CSF is more favourable for, and conducive to brain health.
Filippidis P et al. Cerebrospinal Fluid HIV-1 Escape in Patients With Neurocognitive Symptoms: Pooled Data From a Neuro-HIV Platform and the NAMACO Study. JAIDS Journal of Acquired Immune Deficiency Syndromes 93: 219-228, 2023 (open access).