Zheng J, Lopez A, Erichsen D, Bauer M, Cotter RL, Ryan LA, Williams C, Ghorpade A, Morgello S, Gendelman HE; Conference on Retroviruses and Opportunistic Infections.
Program Abstr 8th Conf Retrovir Oppor Infect Conf Retrovir Oppor Infect 8th 2001 Chic Ill. 2001 Feb 4-8; 8: 44 (abstract no. 4).
Univ of Nebraska Med Ctr, Omaha.
Background: Mononuclear phagocyte (MP; brain macrophage and microglia) activation and neuronal injury are major features of HIV-1 encephalitis (HIVE), the histopathological correlate for HIV-1-associated dementia (HAD). MP activation plays a significant role in disease causation and propagation. However, the mechanism by which MP become activated remains poorly understood. One hypothesis is that chemokines, expressed by neural cells, regulate MP immunity. A newly identified chemokine, fractalkine (FKN), is expressed on neurons, where it can be released in soluble form by extracellular cleavage. Due to its chemotactic properties, this protein may underlie MP recruitment and activation during HAD. Here, we examine whether FKN is produced by neurons and if it affects MP activation following HIV-1 viral protein, gp120, and TNF- alpha mediated neuronal injury. Methods: Neuronal injury was determined by an ELISA for apoptosis and LDH release. FKN expression and production were measured by RT- PCR and ELISA. MP activation was assayed by measuring cytokine and chemokine production, intracellular calcium levels, and protein kinase phosphorylation. HIV-1 progeny virions (IIIB and ADA), gp120 and TNF-alpha induced neuronal apoptosis in human neuronal cultures. Results: ELISAs demonstrated an upregulation of FKN production from the injured neurons, mainly by cleavage from the neuronal membrane. FKN induced migration and activation of human MDM and microglia were shown by assay of cellular chemotaxis and measurements of interleukin-8 and TNF-alpha production, respectively. Importantly, FKN was shown to be upregulated in cerebrospinal fluid from patients with HAD (n = 11), as compared to HIV-1 infected patients without neurological compromise (n = 10, P = 0.02). Conclusions: These results, taken together, demonstrate potential role(s) for FKN in MP migration and activation, both critical events in HAD pathogenesis.
Publication Types:
Keywords:
- AIDS Dementia Complex
- Brain
- Chemokine CX3CL1
- Chemokines
- Chemokines, CX3C
- HIV Envelope Protein gp120
- HIV-1
- Humans
- Macrophages
- Membrane Proteins
- Microglia
- Neurons
- Nitric Oxide Synthase
- Phagocytes
- TNF protein, human
- Tumor Necrosis Factor-alpha
- Virion
- immunology
Other ID:
UI: 102243783
From Meeting Abstracts