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2000 First Web Report
With the advent of more effective highly active antiretroviral therapy (HAART) and thus increased life span of people with AIDS, neurological disorders are becoming a hot topic in AIDS research. In the early days of the epidemic, those infected with the virus could only hope to live for a short time before developing the symptoms of full blown AIDS, and death ensued shortly afterwards. The progress made in treatment in the past two decades has prolonged the lives of people with AIDS, to the point where diagnosis is no longer a sign of imminent debilitation and death, but rather an acknowledgement of a possible long road ahead with the aid of drug cocktails. There is also a strong possibility that the HIV infected person may develop HIV associated dementia after years of living with the disease (1).
HIV associated dementia (HAD) is comprised of a spectrum of conditions from the mild HIV-1 motor cognitive-motor disorder to severe and debilitating AIDS dementia complex. Symptoms begin with motor slowing (2), and may progress to severe loss of cognitive function, loss of bladder and bowel control, and paraparesis . A classification system has been formulated for HIV associated dementia:
Stage 0: Normal
Stage 0.5: Subclinical or Equivocal
Minimal or equivocal symptoms.
Mild (soft) neurological signs.
No impairment of work or activities of daily living (ADL).
Stage 1: Mild
Unequivocal intellectual or motor impairment.
Able to do all but the most demanding work or ADL.
Stage 2: Moderate
Cannot work or perform demanding ADL.
Capable of self-care.
Ambulatory, but may need a single prop.
Stage 3: Severe
Major intellectual disability, or
Cannot walk unassisted.
Stage 4: End-Stage
Disease may result from the direct presence of the virus in the central nervous system, toxins released from the virus, the body's immunological responses, or any number of other factors. Studies have found that non physiological levels of cytokines in the brain may have an effect of enhancing replication of HIV 3. Neurodegeneration is implicated in causing the manifestations of dementia, yet the mechanism for neuronal death or malfunction is unknown as of yet.
A mystery of HIV associated dementia was the fact that the human immunodeficiency virus does not seem to infect neurons. However, the virus has been found to infect astrocytes, a type of glial cell within the brain. In 1998, researchers at Flinders University in Australia and Johns Hopkins University found that patients with more rapidly progressing dementia showed more astrocyte death than slower progressors, who in turn showed more cell death than a control group of HIV patients without dementia 4. This supports the idea that the astrocytes, which provide a major mechanism for removing glutamate from the brain, play a role in dementia. Taken into context, the researchers postulated that the next step in this research should be to determine the effect of the apoptosis of the astrocytes on nerve cells.
It has been postulated that the central nervous system provides a "sanctuary" for the persistance and replication of HIV, independent of peripheral viral activity 5. Many drugs used for treatment of HIV are unable to cross the blood brain barrier, and thus virus is protected 6. The majority of research has supported this idea, however a number of studies have found that viral loads within the central nervous system may be affected by antiretroviral therapy. Issues complicating this matter include a shortage of concrete information about the mechanism for the virus's entry past the blood-brain barrier and into the brain. It has been found that HIV can travel within monocytes (cells which differentiate into macrophages) trafficking into the central nervous system. In the later stages of AIDS, there is may be an influx of monocytes into the brain, triggered by the replication of HIV and the immune activation in the brain. The monocytes not only bring HIV into the brain through the blood brain barrier, but can also act as a reservior for further infection by the virus 7.
These pieces of research logically present answers to some of the questions about the etiology of HIV associated dementia. However, results generated through other research have presented conflicting information. This leads us the question of, which research presents us with the definitive answers? A lack of evidence of one straightforward causal mechanism implies a more complicated etiology and calls for continued multi-disciplinary research on these conditions.
Two articles presented in Science magazine last year exemplify the controversy over the causes of HIV associated dementia and the large amounts of conflicting evidence associated with this. The first, written by Suzanne Gartner, hypothesizes that HIV associated dementia is the result of the influx of infected blood monocytes into the brain during end stage disease, and proposes that under this hypothesis, HIV associated dementia may be controlled peripherally through HAART. She also states that protease inhibitors have led to a decrease in HIV associated dementia, and suggests that this may be a result of better control on HIV replication peripherally. In summary, a major point of the article is that with appropriate HAART, HIV associated dementia will not occur 7.
In a response to this article, Major and colleagues wrote that although HIV seems to be controlled peripherally by drug therapy, many of the antiretroviral drugs have great difficulty penetrating the blood brain barrier, and cannot get into the brain in significant enough levels to affect the viral loads there. Although it is difficult to assay the viral load in the brain while a patient is living, post-mortem studies have supported the idea that the virus does appear to be protected while in the brain, and viral load levels differ from those of the periphery 6. They also state that it is a significant finding that HIV is indeed present in the brain very early in infection, and can establish itself there, as a threat to neurological functioning at any time.
Presently, we are left with more questions than answers on this topic. Is this because of the elusive nature of the nervous system? We are constantly left with gaps in our knowledge about the brain after many years of research, and it seems that this case is no different. The nervous system is arguably the most complex system in the human body, and the human immunodeficiency virus is arguably the one of the most puzzling and difficult medical challenges in recent history. They bring together the knowledge and research methods of neuroscientists, immunologists, virologists, and psychologists, among others, to attempt to detect and piece together all of the elements of this disease 8. The common goal of all of their research is the evolution of a functional working model for the development of therapeutic solutions to put an end to the suffering caused by the HIV virus.
2) Potential Mechanisms of Neurologic Disease in HIV Infection
3) AIDS Dementia Complex
4) Disease Associations Hypothesis Presented on How AIDS Related Dementia Develops
5) Insights Into NeuroAIDS: A Big Mac Attack , from the 7th Confererence on Retroviruses and Opportunistic Infections.
6) HIV-Associated Dementia
7) HIV Infection and Dementia
8) HIV in the Brain: Pathology and Neurobehavioral Consequences , meeting report from National Institutes of Mental Health.
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