Monocytes in HIV Encephalitis

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DESCRIPTION (provided by applicant): 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 1we 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 2we 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.