The spectrum of neurological problems affecting people with HIV is changing in the era of highly active antiretroviral therapy, researchers into HIV’s effects on the central nervous system reported at the recent international conference of Evolving Mechanisms of HIV Neuropathogenesis in the HAART era: Domestic and Global Issues, held in Venice, Italy on April 16, 2007.
“We have gone from seeing a lot of opportunistic infections [of the central nervous system (CNS)] to seeing co-morbid factors… such as drug abuse, HCV, aging, ART, psychiatric conditions,” Dr Eliezer Masliah of the University of California, San Diego told the conference.
“The spectrum of neurocognitive disorders is more mild, more attenuated than it was ten years ago,” Dr Justin McArthur of John Hopkin’s University, another noted HIV neurologist said during the plenary talk at the meeting. Both he and other Dr Masliah agreed that patients are still suffering from a constellation of HIV-associated neurological disturbances (HANDs).
While there was some debate at the meeting over whether there are any well-characterised cohorts of patient who still have progressive HIV-associated dementia (HAD) on effective highly effective antiretroviral therapy (HAART) regimens, many researchers feel it’s more than justified to keep a close eye on chronic HIV infection in the brain, even while the majority of people on treatment remain asymptomatic, given HIV’s propensity to cause neurological damage.
Neurological disturbances before HAART
It’s quite clear that HIV can damage the brain. Very soon after primary HIV infection, HIV, probably in infected monocytes and macrophages, trafficks into the central nervous system, where microglial cells also become infected. Both the infected microglial cells and macrophages produce HIV proteins as well as chemokines and cytokines, that damage neuronal cells and also activate other glial cells to produce a number of toxic factors.
In about 25% of people with HIV, high viral loads in the brain led to morphological changes, the classical condition of HIV encephalitis (HIVE). Imaging showed some degree of cortical atrophy, significant white matter changes and dilatation of the lateral ventricles (frequently, patients had vacuolar myelopathy). Pathology studies found some neuronal loss, multinucleated giant cells, nodules, HIV-infected microglial cells and macrophages in the peri-vascular spaces, and astrogliosis. HIVE was often combined with other opportunistic infections.
Another associated neuropathology that was also observed in people with HIV was a decrease in synaptodendritic complexity “that correlated well with the degree of cognitive impairment.”
Of course, there were also people with HIV who never developed HIVE, significant cognitive impairment or dendritic injury. There were also some people who had HIVE without apparent cognitive impairment (perhaps because their neurons secrete higher amounts of fibroblast growth factor-1 (FGF-1) which appears to be protective). Finally, there were people with cognitive impairment without HIVE — however, they generally did show signs of dendritic injury.
Clinically, people with HAND pre-HAART presented with a spectrum of neurologic signs and symptoms — starting with subtle depressive symptoms, evolving to minor cognitive motor disorder (MCMD). As patients progressed to dementia, they developed sometimes severe memory problems, gait difficulty, mental slowing, depressive symptoms (apathy) and a striking frequency of motor impairment. By this stage, the course of disease (and AIDS) was rapidly progressive with quite a low survival rate several months later.
The impact of HAART
HAART rapidly reversed these symptoms in many patients (although many never completely recovered). Some new HANDs have cropped up, however. Dr Masliah breaks these down into four groups:
- 1) particularly aggressive forms of HIVE and white matter injury that may mostly commonly be due to immune response inflammatory syndrome (IRIS);
- 2) extensive perivascular lymphocytic infiltration that may also be due to IRIS (according to other presentations, this process could possibly contribute to an increased risk of eventual cerebrovascular disease and stroke that has been reported in people with HIV on HAART — particularly as people age or develop diabetes);
- 3) “burn-out” forms of HIVE — where the damage caused by HIV before HAART remains, and the individual’s neurocognitive performance does not improve; and
- 4) HAND-associated with aging. “In many of these patients that are worsening, the age has increased considerably,” said Dr Masliah.
In addition, the prevalence of MCMD seems constant or even increasing in some of the large cohort studies as patients survive longer.
In terms of pathology, “we have seen a decrease in the number of cases with neuronal loss and instead we see more of this synaptodendritic pathology,” said Dr Masliah. “Sometimes we’ve also seen increased astrogliosis in the white matter and cases with perivascular inflammation that might or might not be related to an IRIS kind of process. And then we also see these conditions such as “burnout” where there was, at some point, a productive HIV encephalitis and then it disappeared and more like a scar was left.”
The burnout cases explain why some people never improve completely, while the ongoing synaptodendritic injury could explain the persistent MCMD-like problems such as forgetfulness and trouble concentrating,
But as already noted, few people with HIV who receive HAART in time now develop frank HIV-associated dementia. In fact, the effect of HAART has been so profound that it led to some debate at the meeting about whether progressive dementia is really still a problem.
“I think now to look at people who are adequately treated, you do not see them get progressive neurological disease in any way that’s a public health problem,” said Dr Colin Hall of the University of North Carolina. “Certainly you see deficits, but I have seen no evidence from anyone that there is a progressive continuous deficit in people who are adequately treated. Have you got any group of people who are getting worse today, any group of people who are getting significantly worse when they’re adequately treated systemically?”
From the uproar this comment caused at the meeting, it was clear that most of the neurologists present believed that they do indeed have patients who are getting worse. Of course, because of late diagnosis and late initiation of treatment, some patients do still develop the severe form of HAD, but the fact that very few researchers could describe any sizeable cohort of patients with progressive disease on suppressive HAART — without other factors involved such as IRIS, aging, drug use, or drug resistance — indicated the lack of well characterised cohorts with this problem.
However, Dr Victor Valcour of the University of California San Francisco (UCSF) noted that he does have some patients being followed longitudinally who seemed to have gotten worse.
“Out of 300 that we followed, I can identify about maybe 25 that got worse — a good portion of them with undetectable viral load. We are reluctant to publish that data because an equal number seem to get better. So, there’s a fair amount of variation that occurs in following people longitudinally that may be variability in our measuring techniques or it may actually be real.”
He suspects it’s real, though, because his group has performed studies reporting that HIV DNA in PBMC is higher in individuals with HIV dementia compared to those without dementia in both HAART-experienced and HAART-naïve individuals — and that higher levels of HIV DNA also predicted who would develop progressive disease. In other words, people who progress to dementia appear to have a higher burden of long-lived chronically infected monocytes (which may persist as a reservoir).
One consequence of this chronic infection of the brain could be the persistently altered and worsening synaptodendritic function. Dr Benjamin Gelman of the University of Texas, Galveston reported on a recent discovery that HIV and related inflammation alters the ubiquitin immunoproteasome system (UPS) that controls synaptic protein turnover in the brain. He found altered proteasome hydrolysis and immunoproteasome induction which was highly correlated with HAND in 154 patients.
One of the proteasome’s functions is to cleave viral proteins for presentation on the surface of the cell to the immune system, but according to Gelman’s studies, HIV hijacks the brain proteasomes in order to evade immune surveillance. This has a knock-on effect of also disturbing the processing of old synaptic proteins.
"Brain proteasomes are essential for synapse function, learning, and memory formation,” he told the audience. “Protein turnover regulates synaptic transmission and memory formation.” If the proteasome is totally inhibited, it could lead to brain protein misfolding — which is the hallmark of diseases of senile neurodegeneration, such as Alzheimers.
At present though, most of the altered proteasome function in HIV-infected people appears to be less severe, and the reduced synaptic protein turnover appears to simply reduce synaptic “firing” efficiency. Dr Gelman believes that this is more of a problem “of synapto-dendritic maintenance” rather than permanent damage — and the associated neurocognitive impairment should be easily reversible with a reduction of the chronic HIV infection and inflammation (though in an aging brain, this could become another matter).
Chronically infected cells could also continue to secrete low levels of neurotoxic HIV proteins and possibly stimulate oxidative stress and chronic inflammation.
“Theoretically speaking, although antiretrovirals are good, once the virus has entered the cell and proviral DNA is formed, available ART cannot inhibit the production of early viral proteins, the protease inhibitors only act in a later state,” said Dr Avindra Nath, “so if you were to be believe that these early viral proteins [tat, nef, rev, vpr] play a role in pathogenesis [of neurodegeneration], then you would think that in the appropriate environment and the appropriate susceptible host, you will continue to see some progressive damage, some immune activation from these proteins”
“Having circulating monocytes that are not normal like that certainly can not be good for you,” said Dr Lynn Pulliam, also of UCSF. “So I think you have to keep looking for markers of prediction but also just chronic inflammation.”
But again, it remains hard to quantify just how much this ongoing chronic infection and inflammation contributes to the types of neurological complaints that people with HIV have.
Rise of the comorbidities
Part of the reason, according to Dr Masliah is that an individual’s condition can be confounded by other issues such as severe depression and other frequent mental health problems, drug and alcohol dependence, hepatitis C infection (HCV), and finally the most unavoidable complication of them all: aging.
For instance, severe depression, common among people with HIV, can actually cause significant morphological (and functional) changes in the brain. In a study of 20 patients with HIV, twelve with major depression and eight without, there was significant down-regulation of genes that encode for a variety of synaptic proteins — especially somatostatin. “So, again there is a selective neuronal injury in those cases,” said Dr Masliah.
Dr. Masliah believes there is also very specific neuronal injury in the brains of people with HIV who are also methamphetamine abusers.
“In these individuals we have seen significant damage to these inter-neurons which are the CALBINDIN immunoreactive inter-neurons. This appears to be related to the ability of methamphetamine to stimulate the macrophages and production of interferons, and in turn stimulate interferon-associated genes that could be potentially neurotoxic to neurons.”
Another factor that was noted in many of the methamphetamine users was hepatitis C. “We have studied the individuals in our population that are methamphetamine abusers and that have a history of hepatitis C and we have documented the presence of HCV antigens and mRNA in the brains of these individuals and in particular in astroglial cells,” said Dr Masliah.
Other groups have confirmed these findings, but, while HCV may be present in the brain, it is not yet clear to what extent it contributes to neurological complication. However, it could be one potential explanation for reports of consistently higher rates of neurocognitive impairment in injection drug users.
But perhaps the greatest factor that could reduce neurocognitive performance — or at least that one that affects every patient — is aging. Data were presented at the conference suggesting that a number of age-related neurodegenerative disorders may be accelerated as a consequence of HIV infection.
Go to part four - Will people with HIV be at increased risk of Alzheimer's- or Parkinson's-like diseases as they age?
Everall I.P., Hansen L.A, Masliah. The shifting patterns of HIV encephalitis neuropathology. Evolving Mechanisms of HIV Neuropathogenesis in the HAART era: Domestic and Global Issues, Venice, Italy, 2007.
Gelman B. HIV hijacks the proteasome: implications for altered synaptic transmission. Evolving Mechanisms of HIV Neuropathogenesis in the HAART era: Domestic and Global Issues, Venice, Italy, 2007.
McArthur J. The changing phenotype of HIV dementia in the HAART era: potential mechanisms. Evolving Mechanisms of HIV Neuropathogenesis in the HAART era: Domestic and Global Issues, Venice, Italy, 2007.