HIV infected individuals develop a wide spectrum of neurologic disease ranging from minor cognitive and motor deficits (MCMD) to frank dementia (HIV-associated dementia complex, HIVD). While the pathologic substrate of MCMD is unknown, HIV encephalitis (HIVE) is a known pathologic substrate of HIVD. Abundant activation and infection of CNS macrophages characterize HIVE, with surprisingly little evidence of direct neuroglial infection. The relative role of activated and infected CNS macrophages in mediating neurologic damage is not known. We hypothesize that HIV associated MCMD is related to pathologic activation of macrophages within the CNS. Further this activation provides abundant host target-cells for infection and replication of HIV and subsequent development of HIVE and HIVD. Unfortunately there are no current means of documenting activated macrophages within the CNS. We propose to extend our findings from the simian AIDS model, to humans infected with HIV and test the hypothesis that: the radioligand 11C-PK11195 in 3D-PET will detect the presence of activated macrophages in the CNS of HIV infected subjects. By comparing neurocognitive findings, and peripheral and central markers of HIV infection and PK11195 PET we hope to establish a clinical measure of CNS macrophage activation.
In Specific Aim 1 we will perform a cross sectional study of HIV infected subjects and appropriate controls to determine the relationship between binding of the radioligand 11C-PK11195 in 3D PET imaging and neurologic disease. All subjects will be given a battery of neurocognitive testing: undergo MRI and PK11195-PET imaging and serum testing for HIV titers and CD4 count. We hypothesize that those subjects with MCMD or HIVD will have elevated binding and retention of PK11195 consistent with increased activation of CNS macrophages.
In Specific Aim 2 we will longitudinally follow HIV infected subjects at risk for developing dementia. At 6-month intervals, subjects will undergo a battery of neurocognitive exams, serum and CSF analysis, head MRI and C-11PK11195 PET. We hypothesize that prior to developing neurologic disease associated with activated CNS macrophages, PET scans will demonstrate elevated binding and retention of PK11195. If neurologic disease symptomatology progresses, this will be accompanied by persistent elevation of PKlll95 on 3D PET, Successful therapeutic intervention would be associated with decreased PET signal. The results of these experiments will help define clinical tests for diagnosing lentiviral encephalitis and help identify infected populations at risk of developing neurologic disease. They will also permit the development of markers to assess efficacy of future therapy to arrest development and progression - of MCMD and HIVD.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Special Emphasis Panel (ZRG1-AARR-1 (05))
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Joseph, Jeymohan
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University of Pittsburgh
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Bonneh-Barkay, Dafna; Wiley, Clayton A (2009) Brain extracellular matrix in neurodegeneration. Brain Pathol 19:573-85
Venneti, Sriram; Lopresti, Brian J; Wang, Guoji et al. (2009) PK11195 labels activated microglia in Alzheimer's disease and in vivo in a mouse model using PET. Neurobiol Aging 30:1217-26
Wiley, Clayton A; Lopresti, Brian J; Venneti, Sriram et al. (2009) Carbon 11-labeled Pittsburgh Compound B and carbon 11-labeled (R)-PK11195 positron emission tomographic imaging in Alzheimer disease. Arch Neurol 66:60-7
Venneti, Sriram; Wang, Guoji; Nguyen, Jason et al. (2008) The positron emission tomography ligand DAA1106 binds with high affinity to activated microglia in human neurological disorders. J Neuropathol Exp Neurol 67:1001-10
Bonneh-Barkay, Dafna; Bissel, Stephanie J; Wang, Gouji et al. (2008) YKL-40, a marker of simian immunodeficiency virus encephalitis, modulates the biological activity of basic fibroblast growth factor. Am J Pathol 173:130-43
Bissel, Stephanie J; Wang, Guoji; Bonneh-Barkay, Dafna et al. (2008) Systemic and brain macrophage infections in relation to the development of simian immunodeficiency virus encephalitis. J Virol 82:5031-42
Venneti, Sriram; Wang, Guoji; Wiley, Clayton A (2008) The high affinity peripheral benzodiazepine receptor ligand DAA1106 binds to activated and infected brain macrophages in areas of synaptic degeneration: implications for PET imaging of neuroinflammation in lentiviral encephalitis. Neurobiol Dis 29:232-41
Venneti, Sriram; Wang, Guoji; Wiley, Clayton A (2007) Activated macrophages in HIV encephalitis and a macaque model show increased [3H](R)-PK11195 binding in a PI3-kinase-dependent manner. Neurosci Lett 426:117-22
Venneti, Sriram; Lopresti, Brian J; Wang, Guoji et al. (2007) A comparison of the high-affinity peripheral benzodiazepine receptor ligands DAA1106 and (R)-PK11195 in rat models of neuroinflammation: implications for PET imaging of microglial activation. J Neurochem 102:2118-31
Bissel, Stephanie J; Wang, Guoji; Trichel, Anita M et al. (2006) Longitudinal analysis of monocyte/macrophage infection in simian immunodeficiency virus-infected, CD8+ T-cell-depleted macaques that develop lentiviral encephalitis. Am J Pathol 168:1553-69

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