Most HIV-infected individuals progress to AIDS with 25-30% of infected adults developing a debilitating neurological disorder termed AIDS dementia complex. The pathologic substrate of ADC, designated HIV encephalitis (HIVE), is characterized by perivascular accumulation of macrophages and multinucleated giant cells in the CNS and abundant infection of brain macrophages. It is generally believed that HIV-infected peripheral blood monocytes cross the blood-brain-barrier (BBB) and serve to bring virus into the CNS, however, this has not been unequivocally demonstrated in vivo. This is due primarily to our inability to 1) precisely identify subsets of virus-infected monocytes in the peripheral blood that traffic to the CNS and 2) to differentiate between virus infection of monocyte/macrophages that have recently been recruited to the CNS and virus infection of resident CNS macrophages. We have recently observed that there are distinct subsets of monocyte/macrophages in the CNS of SIV-infected macaques with SIV encephalitis (SIVE) that can be easily distinguished by their expression of myeloid-related proteins (MRP) 8 or MRP14, markers for activated monocyte/macrophages. In addition, MRP8 + and MRP14 + subsets of monocyte/macrophages appear to exhibit differential trafficking and infectivity by SIV. Based on these observations we hypothesize that there are phenotypically distinct subsets of monocyte/macrophages in the rhesus macaque that differ in their expression of chemokine receptors. We hypothesize that MRP8 + cells, and not MRP14 + cells, express CCR5. This would both render MRP8 + monocytes susceptible to SIV infection, and capable of chemotaxis in response to C-C chemokines, which we have previously shown to be abundant in lesions of SIVE. We propose to utilize the SIV/macaque model of neuroAIDS to test our hypotheses and further characterize monocyte/macrophage subsets in healthy and SIV-infected macaques.
Specific Aims i nclude: 1) To quantify numbers and evaluate the immunophenotype of monocyte/macrophage subsets in peripheral blood, lymph node and CNS of uninfected macaques and determine the effect of SIV infection on these parameters. 2) To identify which subset of monocyte/macrophages is infected with SIV in different tissue compartments at different stages of infection. 3) Evaluate the ability of immediately ex vivo monocyte subsets to adhere to brain microvascular endothelial cells and migrate in response to chemotactic stimuli.
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