Lymphotropic Virions Affect Chemokine Receptor-Mediated Neural Signaling and Apoptosis: Implications for Human Immunodeficiency Virus Type 1-Associated Dementia

Authors

Jialin Zheng, University of Nebraska Medical Center
Anuja Ghorpade, University of Nebraska Medical Center
Douglas Niemann, University of Nebraska Medical Center
Robin L. Cotter, University of Nebraska Medical Center
Michael R. Thylin, University of Nebraska Medical Center
Leon Epstein, Northwestern University Medical School, Chicago, Illinois
Jennifer Swartz, University of Nebraska Medical Center
Robin B. Shepard, University of Nebraska Medical Center
Xiaojuan Liu, University of Nebraska Medical Center
Adeline Nukuna, University of Nebraska Medical Center
Howard E. Gendelman, University of Nebraska Medical Center

Date of this Version

October 1999

Comments

Published in JOURNAL OF VIROLOGY, 0022-538X/99/$04.0010 Oct. 1999, p. 8256–8267 Vol. 73, No. 10 Copyright © 1999, American Society for Microbiology. Used by permission.

Abstract

Chemokine receptors pivotal for human immunodeficiency virus type 1 (HIV-1) infection in lymphocytes and macrophages (CCR3, CCR5, and CXCR4) are expressed on neural cells (microglia, astrocytes, and/or neurons). It is these cells which are damaged during progressive HIV-1 infection of the central nervous system. We theorize that viral coreceptors could effect neural cell damage during HIV-1-associated dementia (HAD) without simultaneously affecting viral replication. To these ends, we studied the ability of diverse viral strains to affect intracellular signaling and apoptosis of neurons, astrocytes, and monocyte-derived macrophages. Inhibition of cyclic AMP, activation of inositol 1,4,5-trisphosphate, and apoptosis were induced by diverse HIV-1 strains, principally in neurons. Virions from T-cell-tropic (T-tropic) strains (MN, IIIB, and Lai) produced the most significant alterations in signaling of neurons and astrocytes. The HIV-1 envelope glycoprotein, gp120, induced markedly less neural damage than purified virions. Macrophage-tropic (M-tropic) strains (ADA, JR-FL, Bal, MS-CSF, and DJV) produced the least neural damage, while 89.6, a dual-tropic HIV-1 strain, elicited intermediate neural cell damage. All T-tropic strain-mediated neuronal impairments were blocked by the CXCR4 antibody, 12G5. In contrast, the M-tropic strains were only partially blocked by 12G5. CXCR4-mediated neuronal apoptosis was confirmed in pure populations of rat cerebellar granule neurons and was blocked by HA1004, an inhibitor of calcium/calmodulin-dependent protein kinase II, protein kinase A, and protein kinase C. Taken together, these results suggest that progeny HIV-1 virions can influence neuronal signal transduction and apoptosis. This process occurs, in part, through CXCR4 and is independent of CD4 binding. T-tropic viruses that traffic in and out of the brain during progressive HIV-1 disease may play an important role in HAD neuropathogenesis.