HIV and the Brain
How HIV causes neurocognitive impairment is not fully understood, but likely involves multiple processes such as inflammatory damage to brain cells and blood vessels, vascular dysfunction related to metabolic abnormalities, and acceleration of age-related neurodegeneration.
HIV enters the brain soon after initial infection -- typically within the first several days -- but does not cause significant damage right away. The virus is able to cross the blood-brain barrier, which protects the central nervous system from toxins and other harmful agents, by hiding in immune cells known as monocytes.
Lipopolysaccharide in the blood from bacteria released when HIV damages the gut lining appears to make the blood-brain barrier more permeable ("leakier"), letting in more virus. In a vicious cycle, once inside the brain, HIV triggers an inflammatory response that further disrupts the barrier.
HIV in the brain does not infect neurons, the key cells responsible for transmission of electrical impulses that control the body. A small amount of HIV may enter support cells known as astrocytes and oligodendrocytes, but it does not replicate and produce new virus (these cells may act as a viral reservoir, however).
Instead, the primary target is specialized brain macrophages called microglia, and other cells of the monocyte line (a type of immune cell produced in bone marrow). Once inside these long-lived cells, HIV may remain in a prolonged latent state.
Rather than directly killing brain cells -- as it does with CD4 T-cells elsewhere in the body -- HIV exerts its detrimental neurological effects by setting off a cascade of inflammatory changes. Immune cells activated to fight the virus produce various cytokines (chemical messengers) -- such as interferon-alpha and tumor necrosis factor-alpha -- that in turn activate astrocytes and attract more immune cells to the battlefield.
These chemicals also trigger the release and inhibit the removal of glutamate, an excitatory neurotransmitter that can overstimulate and thereby injure neurons. This proinflammatory cascade disrupts cellular communication channels and promotes damaging oxidative stress.
Furthermore, HIV Tat and gp120 proteins released when the virus replicates appear to have direct neurotoxic effects. One study in mice showed that gp120 also inhibits neurogenesis, or proliferation of new neurons to repair injury.
Examined on autopsy, brains of people with HIV show inflammatory changes, excessive accumulation of astrocytes (known as astrocytosis or gliosis), demyelination (loss of the protective insulation surrounding neuron axons), and build-up of amyloid precursor proteins. Studies have revealed atrophy or abnormalities in various brain regions and structures, including the basal ganglia, hippocampus, and corpus callosum.
Ian Everall and colleagues with the National NeuroAIDS Tissue Consortium looked at autopsy results from nearly 600 HIV patients who had died since 1999, soon after the advent of combination ART. While only about 18% of examined brains showed typical HIV-related brain pathology, most exhibited some other type of abnormality, and only 22% were normal. Interestingly, however, HIV brain pathology did not correlate with the presence of HAND.
Turning to brain imaging in living patients, MRI scans of participants in the CHARTER study showed that neurocognitive impairment was associated with atrophy or loss of gray matter (comprised of neuron cell bodies) and abnormal white matter (largely made up of myelin-covered neuron axons). Using magnetic resonance spectroscopy, Bradford Navia and colleagues with the HIV Neuroimaging Consortium found evidence of inflammation in people with HIV and loss of neurons in people with HAND.
While there is some loss or death of neurons in the brains of people with HIV-related neurological disorders, a more typical finding is damaged neurons with their dendrites "cut off" so they can no longer receive neural impulses (known as synaptic pruning). The fact that some neurons are injured rather than dead may explain why partial reversal of impairment may occur after starting ART.
The end result of this assault on the brain is the spectrum of cognitive, motor, and psychological manifestations that characterize HAND. The extent of this inflammatory response does not appear to be closely correlated with the amount of HIV in the brain. Thus, even among individuals receiving suppressive ART, low-level residual virus may be enough to maintain this neurotoxic environment and its associated impairment.
HIV-related neurocognitive impairment can be difficult to diagnose because its symptoms.such as poor attention, memory lapses, and mood changes. overlap with those of many other conditions (see sidebar).
Brain-related OIs and malignancies are often marked by physical rather than cognitive symptoms. Encephalopathy. a general term for physiological brain disease (while encephalitis more specifically refers to brain inflammation). may cause headaches, seizures, tremors, problems with coordination or balance, and vision or speech disturbances.
Meningitis (inflammation of the membranes covering the brain and spinal cord) typically causes symptoms including headaches, altered mental status, and, most characteristically, stiff neck.
Sudden onset or rapid progression of such symptoms should prompt a thorough examination, especially for HIV positive people with advanced immune suppression. While brain OIs are less common in the ART era, they still occur -- even in wealthy countries -- among people who do not know they have HIV and do not access care until later stages of disease.
A lumbar puncture (spinal tap) may be done to obtain a sample of the cerebrospinal fluid surrounding the brain and spinal cord to test for pathogenic organisms, or a brain biopsy may be performed to extract a sample of tissue to examine under a microscope.
Neuroimaging methods, including computed tomography, MRI, and radiography (X-rays), may reveal characteristic physical features associated with specific OIs. The location and number of lesions -- single or multiple, symmetric or asymmetric, affecting gray or white matter -- can suggest specific causes.
Diagnosing neurocognitive impairment can be more difficult, since HIV-related cognitive disorders -- even frank dementia -- have not been linked to specific, consistent brain imaging findings in most studies (though, as described above, some brain changes can be seen using imaging methods, and characteristic alterations are apparent on autopsy).
Early signs of HIV-related neurocognitive impairment may be so subtle that affected individuals and their families and friends are not aware of them. A wide range of standardized neuropsychological tests are used to identify subclinical deficits in specific functional domains.
These may include tests of psychomotor speed (e.g., finger-tapping test), hand-eye coordination, fine motor control (e.g., grooved pegboard test), ability to register and recall memories, attention and concentration (e.g., trail-making test, color-naming test), problem-solving ability, language abilities (both verbal fluency and comprehension), and visual acuity. There are also numerous tests, such as the Beck Depression Inventory, designed to diagnose psychiatric conditions and assess mood or personality changes.
Cognitive deterioration that happens very slowly over a long period may escape notice until it reaches advanced stages. Symptom checklists, diaries, and functional inventories (e.g., which tasks of daily living a person can perform) may be compared over time to reveal such changes. When evaluating neurocognitive symptoms, it is important to keep in mind what is "normal" for a particular individual.
Researchers have designed tools to specifically diagnose and classify HIV-related neurocognitive impairment -- such as the International HIV Dementia Scale developed by Ned Sacktor and colleagues -- but investigators continue to use a wide variety of instruments, making comparisons across studies difficult.
Experts do not favor running every HIV positive person through a full battery of neuropsychological tests to identify the most subtle deficits. But Letendre recommends that clinicians ask their patients about neurocognitive impairment -- including difficulties carrying out activities of daily living -- if patients do not bring up the subject.
While specialized neurocognitive testing is typically administered by a psychologist, neurologist Greg Pauxtis emphasizes that HIV care providers can do basic cognitive screening using a brief office test such as the Mini-Mental State Examination or Short Test of Mental Status.
It can be particularly challenging to distinguish HIV-related impairment from Alzheimer's disease and other forms of dementia, especially in older individuals who may have features of both.
Classic HAD typically produces more subcortical symptoms such as psychomotor slowing and diminished attention, while Alzheimers's often produces more cortical manifestations such as memory loss and language deficits.
Alzheimer's disease is also characterized by distinctive pathological features, including amyloid or senile plaques and neurofibrillary tangles. As noted above, these features are increasingly observed in people with HIV.
Finally, HIV-related neurocognitive disorders -- unlike Alzheimer's -- are often reversible to some extent with effective ART, though residual impairment may persist long-term.
Markers of HIV disease progression provide useful but limited information. As discussed previously, HIV-related neurological disorders are associated with low CD4 cell count, particularly a low nadir level. But a relatively high CD4 count is no guarantee against neurocognitive impairment.
Immune status can, however, provide diagnostic clues. For example, since people with high CD4 counts seldom develop OIs, neurocognitive or motor symptoms or unusual brain imaging findings in these individuals are more likely to suggest other causes, such as a stroke or a malignant or benign brain tumor.
The association between HAND and HIV viral load in the blood plasma and CSF is subject to debate, due to conflicting study findings spanning more than two decades.
Considerable observational and controlled trial evidence has linked plasma HIV suppression and improved neurocognitive performance. Furthermore, in a recent analysis of patients in the Thai SEARCH 001 study, published in the March 17, 2009, issue of Neurology, Valcour and colleagues found that while plasma HIV RNA levels did not predict HAD, detectable HIV DNA in peripheral monocytes -- an indicator of latent reservoir virus -- was associated with poorer cognitive performance.
In the pre-ART era, high CSF viral load was associated with more severe neurological disorders. Among people receiving suppressive therapy, however, the relationship between CSF HIV RNA level and mild-to-moderate impairment is less clear, and CSF viral load is not a reliable diagnostic tool. Furthermore, HIV levels in the CSF do not necessarily correlate with the amount of virus in brain tissues.
As described below, participants in the CHARTER cohort who had detectable CSF viral load using an ultrasensitive test had both a higher likelihood of neurological impairment and worsening impairment over time. A recent small British study likewise found that detectable HIV RNA in the CNS was associated with neurological deficits among ART-treated patients, despite suppression of viral replication in the plasma.
Other researchers, however, have observed no association between plasma or CSF viral load and prevalence or degree of neurocognitive impairment.
Most experts consider ART the key to preventing and managing HIV-related neurocognitive problems, and epidemiological studies clearly demonstrate declines in brain OIs and severe neurological disorders since the advent of effective combination therapy.
In general, ART reduces HIV RNA in both blood plasma and CSF, but the effect may be more pronounced in one compartment or the other. Furthermore, as discussed below, different drugs vary in their ability to reach virus in the brain. Researchers have not conclusively determined whether antiretroviral drugs must cross the blood-brain barrier in order to protect the brain from HIV-related damage, or whether suppressing viral replication in the blood is adequate.
Numerous studies have looked at the effects of antiretroviral drugs on CSF viral load, while others have gone a step further to assess their influence on brain pathology and neurocognitive performance. As with many aspects of HIV-related neurological disease, this research has yielded mixed results.
Studies showing a beneficial effect date back to the early years of the ART era. In 2001, for example, investigators with the HIV Epidemiological Research Study (HERS) reported that HIV positive women with advanced immune suppression who started combination ART demonstrated improved neurocognitive performance. Women who were on ART the longest demonstrated the greatest improvement, while untreated women continued to decline. Neurocognitive improvement was strongly associated with the magnitude of CD4 cell gains.
More recently, McCutchan reported that in an observational study of more than 400 advanced AIDS patients who experienced good immune recovery after starting combination ART, 27% showed evidence of impairment on neuropsychological tests. This was significantly lower than the expected rate in untreated patients, but still twice that of HIV negative individuals of a similar age.
In the majority of studies that show neurocognitive improvement on ART, advances have been linked to plasma HIV RNA suppression. A team at San Francisco General Hospital, however, found that even patients who had detectable plasma viral load due to failing therapy could experience decreases in CSF viral load, as well as reduced immune activation and inflammation in the CNS.
Swedish investigators found that HIV patients with and without dementia who started ART showed decreased CSF levels of neurofilament protein, a substance associated with neurodegenerative disorders including HAD and Alzheimer's disease; after one year on therapy, 75% had attained normal levels. "HAART seems to halt the neurodegenerative process(es) caused by HIV-1," they concluded.
In a study published in the June 19, 2009, issue of AIDS, Maria Marcondes of Scripps Research Institute and colleagues compared rhesus monkeys newly infected with SIV (a simian virus similar to HIV) that received either no treatment or early (shortly after resolution of acute infection) antiretroviral therapy using tenofovir (Viread) and nelfinavir (Viracept), two drugs with minimal CNS penetration.
Treated monkeys experienced a significant drop in brain viral load, reduced inflammatory response, and improved motor performance. The researchers concluded that "even with agents that show poor penetration into the central nervous system, early antiretroviral treatment prevented characteristic neurophysiological and locomotor alterations arising after infection." They cautioned, however, that this might not be the case with later ART started after brain damage has become established.
On the other hand, some researchers have not seen similar effects, especially among patients with less advanced HIV disease and milder neurocognitive impairment. In 2004, Lucette Cysique and colleagues reported that the overall prevalence of neuropsychological impairment was essentially the same before and after the introduction of combination ART (41% vs 39%, respectively).
The pattern of impairment shifted, however, with improvement in simple attention, verbal fluency, and visuoconstruction (a test of visual/spatial ability), but deterioration in learning efficiency and complex attention. Based on the worsening in some domains, the investigators concluded that the observed deficits did not reflect only leftover past damage, but new injury as well.
An Italian study published in 2006, which looked at 165 patients with relatively well-controlled HIV disease on stable ART regimens (half with baseline neuropsychological impairment, half without), found that use of ART -- including drugs with good CSF penetration -- was not associated with improved neurocognitive performance.
More recently, a study from Argentina looked at 260 HIV patients (158 on ART with viral load below 1,000 copies/mL and 102 treatment-naive) with a CD4 count above 350 cells/mm3; the mean age was 38 years. While younger participants performed better on the International HIV Dementia Scale, scores did not differ significantly between patients on and off combination ART.
Overall, the most frequent finding is that ART restores neurocognitive function -- especially in patients most severely impaired when starting treatment -- but not to the level of HIV negative people. Many studies, however, did not distinguish between regimens with more or less CNS penetration. Does persistent impairment reflect irreversible brain damage, or does it indicate that the drugs are not getting where they need to go?
This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.
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