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HIV Associated Neurocognitive Disorders

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Abstract
Infection with HIV continues to be a major public health concern. Although
treatment with HAART has dramatically improved outcomes for patients infected
with HIV, there are still significant neurological consequences related to HIV
infection, particularly the HIV-associated neurocognitive disorders (HAND). While
the incidence of HAND has decreased with HAART, the prevalence has increased. As
life expectancies for HIV-infected patients increases, clinicians must be alert to the
signs and symptoms of neurocognitive decline in these patients. While current
treatment is an effective HAART regimen, appropriate assessment of neurocognitive
decline in HIV-patients is essential for both the health status and quality of life of the
patient. Research is ongoing in the neurologic effects of HIV infection, ranging from
more effective CNS drug delivery to identifying biomarkers that can be used as
predictors of HAND.

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Infection with human immunodeficiency virus (HIV) continues to be a major
public health concern. According to the most recent report released by the Joint
United Nations Programme on HIV/AIDS (UNAIDS), an estimated 33.3 million
people worldwide are infected with HIV, with approximately 1.2 million in the
United States1. In the US, there were approximately 54,000 new infections and
17,000 deaths in 20091. There have been remarkable advances in the
understanding of both the life cycle of the virus and its pathogenesis, with the
accompanying development of effective treatments for HIV infection, making HIV a
potentially chronic disease. However, there are still significant consequences to
chronic HIV infection. In particular are the neurological conditions related to HIV,
most commonly a distal sensory polyneuropathy, and the HIV-associated
neurocognitive disorders, or HAND2. With the development of highly active
antiretroviral treatment (HAART), the incidence of many acquired
immunodeficiency syndrome (AIDS) associated diseases, including neurocognitive
disorders, showed a significant decrease3. However, even with effective HAART,
some level of neurologic impairment is seen in anywhere from 50-70% of patients
with HIV disease4, and with longer life expectancies in HIV+ patients, the prevalence
of HAND, particularly the milder forms, also continues to increase2,5. Although some
factors, including extremes of patient age, high viral loads and thrombocytopenia6,
low CD4+ cell counts, previous AIDS diagnosis, and a longer duration of HIV disease,
have been associated with an increased risk of neurocognitive deficit3, a complete
understanding of the pathologic mechanisms is still unclear and is an area of
ongoing investigation.

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An appreciation of the pathogenesis of systemic HIV infection is important in
understanding the mechanism of central nervous system (CNS) infection. HIV is a T
lymphotrophic retrovirus containing two copies of single-stranded RNA that is
spread through sexual contact, exposure to blood or blood products from IV drug
use or transfusions, and through vertical transmission from mother to fetus. HIV
preferentially infects both T cells and macrophages because of the binding of the
viral surface protein gp120 to CCR5 and/or CXCR4 co-receptors on CD4+ host cells7.
After entering the host cell, HIV then uses various mechanisms, including enzymes
such as reverse transcriptase and integrase, to incorporate its own genetic material
into that of the host cell7. Following initial infection, most patients have an acute
viral syndrome due to the vigorous viral replication that is occurring8. Without
treatment, plasma viremia peaks approximately one month after the initial infection
and subsequently declines to a viral set point that remains detectable, reflecting
continuous viral replication8. The viremia of acute infection is controlled, although
incompletely, by CD8+ T cells along with B cells producing anti-HIV antibodies9.
Following this, patients not receiving treatment generally remain asymptomatic for
several years before the immune system suffers massive depletion and progression
to the severe immunosuppression that characterizes AIDS.
Also occurring early in infection is significant damage to the gut-associated
lymphatic tissue (GALT), an essential component of the barrier function of the GI
tract10. Massive depletion of gut lymphocytes disrupts the functional ability of the
GI tract causing translocation to plasma of products such as lipopolysaccharide
(LPS), shown to be essential in creating an environment of chronic immune

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activation10. This chronic activation is essential both for continued viral replication
as well as the persistent inflammatory state that is likely responsible for progressive
immune system dysfunction, exhaustion and subsequent progression to AIDS8,11,12.
HIV infection of the CNS occurs early in the disease process. Essential to this
is the infected macrophage, which has the ability to cross not only blood-tissue
barriers, but the blood-brain barrier (BBB) as well7, making infected macrophages
an efficient delivery system of virus to all parts of the body. In addition to the ability
of the macrophage to cross the BBB, bringing HIV to the CNS, the integrity of the
BBB has been shown to be disrupted from infection with HIV. The primary
constituents of the BBB are brain microvascular endothelial cells (BMEC), which
have been shown to be subject to more frequent apoptosis in HIV infected
individuals, resulting in functional distortion of the BBB13. Once established in the
CNS, local and systemic proinflammatory mediators such as tumor necrosis factor(TNF- ) and interleukins 1 and 6 (IL-1 and IL-6) cause further disruption of the
BBB, allowing continued influx of leukocytes and setting up an environment of
neurotoxicity and neurodegeneration14. In the brain, HIV does not directly infect
neurons, only macrophages and microglia, cells that express CD4 receptors15, but is
able to cause indirect neuronal injury through the general inflammatory and
activated immune setting16 as well as through neuronal exposure to neurotoxic viral
proteins such as gp120 and Tat17. Along with the general neurocytotoxicity of the
various viral proteins, gp120 has been shown to increase BBB permeability and
amplify the movement of monocytes across the BBB18. Tat, a regulatory
transactivator protein essential for effective viral transcription, also increases BMEC

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permeability19, can cause oxidative stress in cells, and may be able to induce
neuronal apoptosis20. Tat has also been shown to increase the expression and
secretion of several chemokines that enhance migration of microglia to uninfected
areas of the CNS, continuing a cycle of cell activation, infection and viral
proliferation21. Recent studies have also found that the persistent inflammation
associated with HIV infection can cause disruption of the proteasome system in the
brain, responsible for cellular protein turnover, which can lead to an imbalance of
neuronal synaptic proteins, likely contributing to the development of
neurocognitive dysfunction22.
The research definitions and classification of HAND have recently been
updated to reflect a better understanding of these disorders and the changes in
presentation, incidence and prevalence due to HAART23. The current categories are:
HIV-associated asymptomatic neurocognitive impairment (ANI), essentially a
subclinical picture of minor, non-disruptive impairment; HIV-associated mild
neurocognitive disorder (MND), a category indicating some mild functional
impairment; and HIV-associated dementia (HAD), the most severe and debilitating
manifestation of the disease23. Other terms used for HAD are AIDS dementia
complex (ADC) and HIV encephalopathy (HIVE)24. The most important factor in all
of these categories is the exclusion of any other cause that might be responsible for
the impairment, i.e., other CNS infection, comorbid psychiatric conditions,
cerebrovascular disease, etc.23,25.

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Diagnosis of HAND can be a challenge to the clinician. There is no single
laboratory test for diagnosing HAND. Instead, it is a clinical diagnosis, representing
a collection of varying degrees of neurologic disturbance in HIV-positive patients,
affecting behavior, motor function and cognition12,25. The first category, ANI, is
likely the most difficult to diagnose accurately because of the absence of apparent or
reported functional deficit, although ANI constitutes an estimated 50% of diagnosed
HAND and up to 30% of undiagnosed, asymptomatic HIV-positive patients26.
Although there are many different neuropsychological tests that can be utilized to
evaluate HAND27, simple, standardized tests such as the Modified HIV Dementia
Scale (MHDS)28 or the International HIV Dementia Scale (IHDS)29 are helpful
screening tests for use in HIV-positive patients. The HIV Dementia Scale (HDS) is a
good screening test for patients suspected of more advanced HAND30. The second
category, MND, requires identification of impairment both in cognition and
functioning in areas such as activities of daily living or difficulties with employment
responsibilities26. Self-assessment tests of cognitive functioning, and family, friends
or self-reports of decline are useful in this setting. The last category, HAD, represent
the most devastating outcome of HAND. HAD is characterized by severe cognitive
decline and dysfunction, including mental slowing, memory impairment, gait
disturbance, tremor and difficulties with fine motor movements12. As mentioned
earlier, appropriate diagnosis must exclude other potential disease processes, i.e.,
cryptococcosis, tuberculosis, or CMV encephalitis, common opportunistic infections
in patients with advanced HIV disease31. Imaging is helpful, particularly in ruling
out other infectious lesions, with CT and MR imaging being the most common

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modalities. In general, the most common imaging findings associated with HAD are
cerebral atrophy (either central or peripheral) and white matter lesions (diffuse or
focal)32.
A current area of research concerns the identification of potential blood or
CSF biomarkers that could be used as predictors of HAND, as well as helping to
exclude other possible disease processes that might play a part in neurocognitive
dysfunction33, assisting in a more effective assessment of the disorder. Both plasma
and CSF HIV RNA levels have been shown to be neither specific nor sensitive in
predicting neurocognitive dysfunction33,34, although elevated levels of CSF HIV RNA
may have predictive value in patients receiving HAART33. Other studies have
examined circulating proteins, i.e., chemokines and cytokines. A recent three-year
study found that levels of monocyte chemoattractant protein-1 (MCP-1) were a
useful correlate to both initial and progressive brain injury35. Another study has
examined protease resistant protein, cellular isoform (PrPc), a nonpathological
protein expressed in the CNS and involved in various normal cellular events in the
CNS36. The results showed that levels of PrPc in the CSF were significantly elevated
in HIV-infected patients showing neurocognitive impairment, and thus may be a
useful predictor for HAND36. Ongoing proteomic research involving detailed
analysis of CSF (beyond the scope of discussion here) also holds great potential for
identification of novel and specific biomarkers related to HAND37,38. However, while
identifying single biomarkers is of obvious importance, a clinical picture involving
several markers together may provide a more accurate predictive model39.

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Currently the primary treatment for HAND is an effective regimen of HAART
that results in long-term viral suppression with an attending increase in CD4+
lymphocytes and improved immune function40. However, one of the major
shortcomings of this treatment remains the variable penetrance of the antiretroviral
drugs used in these regimens and the poorer control of CNS HIV with drugs that do
not penetrate the CNS effectively41. Research has been done to classify the available
antiretrovirals according to their CNS penetration42. The drugs with the best
penetration are ones that are rarely, if ever, used in contemporary regimens (i.e.,
zidovudine, nevirapine and indinavir) and some of the most effective drugs with low
side effect profiles (raltegravir and etravirine) have poorer CNS penetration
profiles42. This classification may help to explain the therapeutic gap (a partial
reversal only of neurocognitive deficit) observed in patients on HAART, but it is
likely only a partial explanation, with the inflammatory effects of HIV making a
substantial contribution to neuropathology, as discussed earlier. Even though the
complete benefits of using a regimen based on CNS antiretrovirals are still unclear
and lacking empirical evidence, HAART continues to have a marked impact on the
decline of HAND and other HIV-associated CNS infections43. While some data have
suggested that there may be no benefit for patients without existing neurocognitive
impairment to use HAART regimens with more CNS penetrance and effect44, earlier
treatment of asymptomatic patients with these types of therapy may prevent or
defer the development of HAND, an essential factor to consider as research
continues in drug development41.

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Other than HAART, current research is examining the potential for other
pharmaceutical options for treating HAND. Some evidence exists for the potential
use of antioxidant enzymes (Cu/Zn superoxide dismutase and glutathione
peroxidase)45 as well as selegiline (a monoamine oxidase B inhibitor)46 as
neuroprotective agents against the toxic effects of tat. Minocycline, a tetracycline
antibiotic derivative, has been shown to have some potentially anti-inflammatory
effects in the CNS, excellent BBB penetration, along with neuroprotective effects in
other CNS insults and disease46, and perhaps more importantly, has been show to
inhibit in vitro HIV replication47, making it an exciting possibility for targeted CNS
therapy. Other therapeutic research concerns more effective delivery of drugs to
the CNS while maintaining high activity of the drug48, as well as ways to target the
latent reservoirs of HIV (CNS or otherwise) in an effort to eradicate HIV from the
patient49,50.
Essential for clinical practice is an understanding of the potential
contributions of common comorbidities with HIV infection to neurocognitive
impairment, in particular, substance abuse and co-infection with hepatitis C virus51.
Both substance abuse52 and hepatitis C co-infection, either of which can cause
neurocognitive deficits on their own, are common in HIV-infected patients, with a
hepatitis C infection prevalence of up to 30% in HIV patients53. Various studies have
demonstrated the detrimental impact of concurrent hepatitis C infection54,55 and
substance abuse52,55,56 on both HAND and the acceleration of HAD. This appears to
be particularly important in methamphetamine use, not only for the risk factors that
coexist in this population, but because of the apparent ability of methamphetamine

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to enhance HIV infection of target cells, particularly macrophages57. This should
serve to underscore the importance of appropriate preventative strategies and
interventions for substance abuse and chronic co-infections when treating HIV
patients.
HAND is a common complication in HIV disease. As life expectancies for HIVinfected patients and the prevalence of HAND increase, it becomes more important
for clinicians to have a heightened awareness of the signs and symptoms of
neurocognitive decline. As new and more effective antiretroviral treatments
continue to be developed, therapies that more successfully target HIV in the CNS can
be developed and refined as well, helping improve the outcomes for patients with
HIV disease.

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