Lymphotropic virions affect chemokine receptor-mediated neural signaling and apoptosis: Implications for human immunodeficiency virus type 1- associated dementia

Jialin C Zheng, Anuja Ghorpade, Douglas F Niemann, Robin L. Cotter, Michael R. Thylin, Leon Epstein, Jennifer M. Swartz, Robin B. Shepard, Xiaojuan Liu, Adeline Nukuna, Howard Eliot Gendelman

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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-l-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-triphosphate, 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.

Original languageEnglish (US)
Pages (from-to)8256-8267
Number of pages12
JournalJournal of virology
Volume73
Issue number10
StatePublished - Sep 29 1999

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dementia
Chemokine Receptors
Human immunodeficiency virus 1
virion
Virion
Dementia
HIV-1
apoptosis
neurons
Apoptosis
tropics
Neurons
Virus Diseases
Macrophages
astrocytes
Astrocytes
macrophages
Calcium-Calmodulin-Dependent Protein Kinase Type 2
T-lymphocytes
T-Lymphocytes

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Lymphotropic virions affect chemokine receptor-mediated neural signaling and apoptosis : Implications for human immunodeficiency virus type 1- associated dementia. / Zheng, Jialin C; Ghorpade, Anuja; Niemann, Douglas F; Cotter, Robin L.; Thylin, Michael R.; Epstein, Leon; Swartz, Jennifer M.; Shepard, Robin B.; Liu, Xiaojuan; Nukuna, Adeline; Gendelman, Howard Eliot.

In: Journal of virology, Vol. 73, No. 10, 29.09.1999, p. 8256-8267.

Research output: Contribution to journalArticle

Zheng, Jialin C ; Ghorpade, Anuja ; Niemann, Douglas F ; Cotter, Robin L. ; Thylin, Michael R. ; Epstein, Leon ; Swartz, Jennifer M. ; Shepard, Robin B. ; Liu, Xiaojuan ; Nukuna, Adeline ; Gendelman, Howard Eliot. / Lymphotropic virions affect chemokine receptor-mediated neural signaling and apoptosis : Implications for human immunodeficiency virus type 1- associated dementia. In: Journal of virology. 1999 ; Vol. 73, No. 10. pp. 8256-8267.
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AU - Niemann, Douglas F

AU - Cotter, Robin L.

AU - Thylin, Michael R.

AU - Epstein, Leon

AU - Swartz, Jennifer M.

AU - Shepard, Robin B.

AU - Liu, Xiaojuan

AU - Nukuna, Adeline

AU - Gendelman, Howard Eliot

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