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Session 15 Oral Abstract Session Neuropathogenesis Session Time: Tuesday, 10 am - 12:30 pm Room 606-609

10:45   64. Expression and Functional Analysis of CXCR4 in the Central Nervous System J. Wang* and D. Gabuzda Dana-Farber Cancer Inst., Boston, MA Background: HIV-1 infection of the central nervous system (CNS) causes dementia and other neurological abnormalities in adults and children with AIDS. To better understand the role of HIV-1 co-receptors in neuropathogenesis, expression, and function of CXCR4 on primary human brain cells (HBC) were investigated. Methods: >80 monoclonal antibodies were screened by FACS analysis and immunohistochemistry to characterize cell surface characteristics of neurons and astrocytes. A novel system was established to immunophenotypically characterize neuron and astrocyte subsets and investigate expression and function of CXCR4 in the CNS. Results: CXCR4 was shown to be selectively expressed on an immunophenotypically identifiable neuronal subset and the majority of astrocytes after short-term culture. After prolonged culture, CXCR4 expression was maintained on a subset of neurons but gradually diminished on astrocytes. FACS analysis using a panel of conformation-dependent CXCR4 monoclonal antibodies suggested that CXCR4 has different antigenic conformations in neurons and astrocytes, possibly resulting from different post-translational modifications. IL-1beta and TNF-alpha up-regulated CXCR4 expression on astrocytes but not neurons. IL-1beta, TNF-alpha, and CXCR4-tropic HIV-1 virions induced neuronal apoptosis but their effects were additive rather than synergistic, suggesting that up-regulation of CXCR4 expression on astrocytes did not increase neuronal susceptibility to HIV-1 gp120 neurotoxicity. Several lines of evidence suggested that CXCR4 is expressed and functional on neural stem cells (NSC), including co-expression of CXCR4 and NSC markers, and inhibition of neurosphere formation in a neurosphere-initiation cell (NS-IC) assay by CXCR4 antagonists. Conclusions: These results suggest that interactions between HIV-1 virions and CXCR4 expressed on a subset of neurons, astrocytes, and NSC contribute to neurodegenerative mechanisms in HIV-1 infection and raise the possibility that different CXCR4 conformations on neurons and astrocytes may underlie some cell-type-dependent functions of chemokine receptors in the CNS.

©2002 9th Conference on Retroviruses and Opportunistic Infections