Studies of Brain Infection With the AIDs Virus Suggest Opportunities for Neuroprotection in Other Neurologic Conditions in Children Child's Doctor Fall 2000.

Studies of Brain Infection With the AIDs Virus Suggest Opportunities for Neuroprotection in Other Neurologic Conditions in Children

LEON G. EPSTEIN, MD

aFall 2000

CLINICAL AND NEUROPATHOLOGICAL FINDINGS IN HIV-1 INFECTION

HIV-1, the virus that causes AIDS, also invades the central nervous system (CNS) and results in injury to neurons. In adult patients the clinical presentation is usually a combination of cognitive, motor, and behavioral dysfunction,[1] often associated with MRI or CT evidence of cortical atrophy and disproportionate loss of volume in the basal ganglia. The counterpart in infants and children is the loss of developmental milestones, symmetrical pyramidal (or extrapyramidal) motor abnormalities, and impaired brain growth, manifest as acquired microcephaly (Figure 1).[2] These clinical and neuroradiological features suggest damage to the dendritic arbor and/or death of selective populations of vulnerable neurons.

FIGURE 1 Impaired brain growth in an infant with HIV-1 infection. Children with HIV-1 infection have a normal head circumference at birth but show a deceleration in the rate of head growth by four months and, as demonstrated in this example, become microcephalic (>2SD below the mean) by six to eight months of life. This particular case occurred prior to the availability of effective anti-retroviral therapy but is plotted on a current head growth chart for purposes of illustration. Source: National Center for Health Statistics with the National Center for Chronic Disease Prevention and Health Promotion (2000).

The neuropathological findings in HIV-I infection in children and adults confirm the presence of neuronal injury with simplification of the dendritic arbor and neurons undergoing programmed cell death (apoptosis).[3] This neuronal injury is associated with findings of productively infected blood-derived macrophages and resident microglia, restricted (aborted) infection in astrocytes, the supporting cells in the brain, and widespread activation of the immune system of the brain (microglia).[4,5] (Figure 2).

FIGURE 2 A: Multinucleated giant cells (see arrows) in the brain are formed from fused HIV-1 infected macrophages and perivascular microglia. B: Several HIV-1 infected and activated brain microglia are demonstrated using antibody to HIV-1 p24 protein. C: Astrocytes harboring restricted HIV-1 infection are shown with immunocytochemisty for the HIV-1 regulatory protein Nef. Nef protein is overexpressed in these cells, but no viable viral progeny are produced. D: Productively infected brain macrophage containing HIV-1 structural protein p24 (red immunostain) are shown in proximity to nuclei of basal ganglia neurons stained black using the TUNEL method to identify cells undergoing programmed (apoptotic) cell death.

EXCITOTOXICITY AS THE PATHOGENIC MECHANISM IN HIV-1 INDUCED NEURONAL INJURY

It is important to note that neurons are not susceptible to HIV-1 infection.[1] Findings from numerous investigators have suggested that neuronal injury is caused by an indirect mechanism. It has been proposed that either viral proteins (gp120, Tat, Nef) or pro-inflammatory mediators and cytokines (PAF, TNF-α) released from infected and activated microglia are responsible for neuronal injury[1] (Figure 3).

FIGURE 3 In this schematic drawing, the HIV-1 infected macrophage is the source of multiple neurotoxins including the HIV-1 proteins gp120 and Tat, as well as the inflammatory mediators platelet activating factor (PAF), and tumor necrosis factor-alpha (TNF-a ). All can cause excitotoxicity via the glutamate receptors (NMDA-R). In addition, PAF can depolarize neurons directly via a PAF receptor (PAF-R). TNF-a and the HIV-1 protein Nef inhibit the high-affinity glutamate re-uptake system in astrocytes, exacerbating glutamate mediated neuronal injury.

The final common pathway for neuronal damage appears to be glutamate-mediated excitotoxicity. This mechanism has been implicated in neuronal death in a number of CNS processes including stroke, motor neuron disorders, Parkinson, and Huntington disease. Glutamate is an excitotoxic amino acid (EAA) neurotransmitter that is normally present in brain but is tightly controlled to hold down the excitatory stimulus. Normally it is released in very small amounts and taken up by astrocytes immediately after acting on neuronal receptors. Excessive concentrations of glutamate may cause excitotoxic injury to neurons because of the neurons’ diminished ability to maintain membrane depolarization or metabolic integrity. This condition, often referred to as weak excitotoxicity,[1,6] occurs in acute situations such as brain ischemia or in more chronic conditions. The HIV-1 proteins gp120 and Tat, as well as the inflammatory mediators PAF and TNF-α, act via glutamate receptors or by other signaling pathways to increase oxidative stress in neurons.1 TNF-α and restricted HIV-1 infection of astrocytes independently impair the high-affinity uptake of glutamate by these cells.[5,7] Excitotoxicity and/or oxidative stress ultimately lead to gene-directed neuronal death or apoptosis[1] (Figure 4).

FIGURE 4A HIV-1 may cause excitotoxic injury through the release of a number of neurotoxic viral proteins or cellular cytokines that act either directly via glutamate receptors or sensitize neurons to weak excitotoxicity by increasing oxidative stress. If sustained, this injury ultimately activates cellular pathways leading to apoptotic cell death.

EXCITOTOXICITY IN THE DEVELOPING NERVOUS SYSTEM

Excitotoxic neuronal injury may be particularly important in the developing nervous system where exuberant synaptogenesis and pruning needs to occur in the early post-natal period, largely dependent on excitatory amino acid neurotransmitters.[8,9] EAA neurotransmitters such as glutamate play a critical role in dendritic differentiation, synaptogenesis, and activity-dependent plasticity.[8,9] In the human striate, cortex synaptogenesis is most rapid between two and four months of age.[8] The susceptibility to excitotoxic injury varies during brain development, with greatest vulnerability during periods of robust synaptogenesis when receptors for EAA are over-expressed. Sub-toxic levels of glutamate cause selective inhibition in dendritic outgrowth and dendritic pruning, whereas higher glutamate levels result in cell death. This vulnerability of the developing nervous system probably explains the neuronal injury and impaired brain growth observed in infants with HIV-1 infection.

THERAPEUTIC STRATEGIES USED FOR HIV-1 INDUCED NEURONAL INJURY

The use of anti-retroviral medications, including combination regimens of reverse transcriptase and protease inhibitors, have decreased the incidence of dementia in adults and appear to preserve normal head growth in HIV-1 infected infants. In addition to the use of antiviral therapies, a number of randomized placebo-controlled Phase I/II clinical trials have been conducted using compounds with anti-inflammatory, anti-oxidant, glutamate receptor antagonist or anti-apoptotic properties as potential neuroprotective compounds, with preliminary evidence of efficacy.[10] Larger trials designed to assess the long-term efficacy of these neuroprotective compounds are still needed.

THE FUTURE APPLICATION OF NEUROPROTECTIVE STRATEGIES TO OTHER DISORDERS IN CHILDREN

Modifying excitotoxic injury to neurons may well prove useful in infants and children with other disorders that affect the nervous system. Excitotoxic injury has been implicated in hypoxic-ischemic injury in the neonate and may contribute to both the refractory seizures that occur in this condition during this period and to the poor long-term outcomes that often result. A number of potential therapies including hypothermia and the use of anti-epileptic medications with additional neuroprotective properties are under investigation by neurologists at Children’s Memorial Hospital. In addition, more subtle but significant neuronal injury to the vulnerable developing nervous system may occur during the advanced therapies now applied in the context of bone marrow and solid organ transplantation, as well as in the course of therapy for brain and other neoplasms. In these cases, there may be opportunities for prophylactic therapies for neuroprotection. The hope of these therapies is to improve long-term cognitive outcomes and quality of life in children with a wide range of complex medical conditions that have in common the potential for neuronal injury.

REFERENCES

1. Epstein, LG, Gendelman HE: Human immunodeficiency virus type 1 infection of the nervous system: Pathogenetic mechanisms. Ann Neurol 1993;33:429–436.

2. Epstein LG, Sharer LR, Oleske JM, Connor, EM, Goudsmit J, Bagdon L, Robert-Guroff M, Koenigsberger MR: Neurologic manifestations of human immunodeficiency virus infection in children. Pediatrics 1986;78:678–687.

3. Gelbard HA, James HJ, Sharer LR, Perry SW, Saito Y, Kazee AM, Blumberg BM, Epstein LG: Identification of apoptotic neurons in post-mortem brain tissue from pediatric patients with HIV-1 encephalitis and progressive encephalopathy. Neuropathol Appl Neurobiol 1995;21:208–217.

4. Sharer, LR: Pathology of HIV-1 infection of the central nervous system: A review. J Neuropathol Exp Neurol1992;51:3–11.

5. Saito Y, Sharer LR, Epstein LG, Michaels J, Mintz M, Louder M, Golding K, Cvetkovich TA, Blumberg BM: Over expression of Nef as a marker for restricted HIV-1 infection of astrocytes in postmortem pediatric central nervous tissue. Neurol 1994;44:474–481.

6. Albin RL, Greenamyre JT, Alternative excitotoxic hypotheses. Neurol 1992;42;733–738.

7. Fine SM, Angel RA, Perry SW, Epstein LG, Dewhurst S, Gelbard HA: Tumor necrosis factor alpha inhibits glutamate uptake by primary human astrocytes: Implications for pathogenesis of HIV-1 dementia. J Biol Chem 1996;271:15303–06.

8. McDonald JW, Johnston MV: Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res Rev 1990;15:41–70.

9. Rakic P, Bourgeois JP, Eckenhoff MF, Zecevic N, Goldman-Rakic RS: Concurrent overproduction of synapses in diverse regions of the primate cerebral cortex. Science 1986;232:232–235.

10. Dana Consortium on the Therapy of HIV Dementia and Related Cognitive Disorders: A randomized, double-blind, placebo-controlled trial of deprenyl and thioctic acid in human immunodeficiency virus-associated cognitive impairment. Neurol 1998;50:645–651.

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