8th Conference on Retroviruses and Opportunistic Infections Chicago, IL - February 4 - 8, 2001

Conf Retroviruses Opportunistic Infect 2001 Feb 4-8; 8:44 (abstract no. 4)

J. Zheng¹, A. Lopez¹, D. Erichsen¹, M. Bauer¹, R. L. Cotter¹, L. A. Ryan¹, C. Williams¹, A. Ghorpade¹, S. Morgello², and H. E. Gendelman^1
1Univ. of Nebraska Med. Ctr., Omaha and ²Mt. Sinai Med. Ctr., New York, NY

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-α 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-α 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-α 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.

2001-02-04
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Copyright © 2001 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.