Neurologic abnormalities in HIV-1-infected children are considered to be more sever than in adults with a different spectrum of manifestations. The reasons for these differences are obscure. A likely explanation is the immaturity of the host, specifically the developmental state of the CNS and immune system. In support of this general thesis, we have recently observed significant differences in the pathogenesis of SIV in neonatal vs. adult macaques. In the CNS, the primary differences were in the frequency of infection of monocyte/macrophage/microglia. We hypothesize that these differences are related to the """"""""maturity"""""""" of neonatal monocyte/macrophages and their ability to support SIV replication and/or the selective recruitment and retention of mononuclear cells in the CNS. Unifying these apparently disparate possible explanations is the expression of chemokine receptors, particularly CCR5. Furthermore, CCR5 and other chemokine receptors have been demonstrated on neurons suggesting that CCR5 and related molecules may play important roles at multiple steps in the neuropathogenesis of AIDS. To examine our hypothesis and the role of chemokine receptors in the neuropathogenesis of pediatric AIDS we will use the SIV/macaque model to 1). Examine the role of viral determinants in neuroinvasion and neurovirulence in neonatal macaques inoculated at birth. 2). Examine the role of host factors responsible for neuroinvasion and neurovirulence of HIV infection in neonatal macaques by a). Examining the sequential expression of leukocyte and endothelium derived adhesion molecules, and chemokines in the brain and correlate their expression with the onset of cellular infiltrates and SIV infection of the CNS; b). Analyze the regional and cellular distribution of chemokine receptor expression in brains of neonatal SIV-infected rhesus macaques at different stages of disease compared to uninfected controls and c). Characterize chemokine receptor expression in immediately ex vivo populations of brain macrophages from SIV-infected and uninfected macaques and examine their ability to support SIV infection.
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