Lymphotropic virions affect chemokine receptor-mediated neural signaling and apoptosis: implications for human immunodeficiency virus type 1-associated dementia.
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.
Zheng
J
J
Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198-5215, USA.
Ghorpade
A
A
Niemann
D
D
Cotter
R L
RL
Thylin
M R
MR
Epstein
L
L
Swartz
J M
JM
Shepard
R B
RB
Liu
X
X
Nukuna
A
A
Gendelman
H E
HE
D015526:AIDS Dementia Complex / Q000378:metabolism* / Q000821:virology*; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D015497:HIV-1; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism / Q000821:virology; D009474:Neurons / Q000378:metabolism* / Q000821:virology*; D051381:Rats; D019707:Receptors, Chemokine / Q000378:metabolism*; D015398:Signal Transduction; D014771:Virion / Q000502:physiology*
D019707:Receptors, Chemokine; D015544:Inositol 1,4,5-Trisphosphate