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 expre ssed on neural cells (microglia, astrocytes, and/or neurons). It is these c ells which are damaged during progressive HIV-1 infection of the central ne rvous system. We theorize that viral coreceptors could effect neural cell d amage during HIV-1-associated dementia (HAD) without simultaneously affecti ng viral replication. To these ends, we studied the ability of diverse vira l strains to affect intracellular signaling and apoptosis of neurons, astro cytes, and monocyte-derived macrophages, Inhibition of cyclic AMP, activati on of inositol 1,4,5-trisphosphate, and apoptosis were induced by diverse H IV-1 strains, principally in neurons. Virions from T-cell-tropic (T-tropic) strains (Mn, IIIB, and Lai) produced the most significant alterations in s ignaling of neurons and astrocytes. The HIV-I envelope glycoprotein, gp120, induced markedly less neural damage than purified virions. Macrophage-trop ic (M-tropic) strains (ADA,;IR-FL, Bal, MS-CSF, and DJV) produced the least neural damage, while 89.6, a dual-tropic HIV-1 strain, elicited intermedia te neural cell damage. All T-tropic strain-mediated neuronal impairments we re blocked by the CXCR4 antibody, 12G5. In contrast, the M-tropic strains w ere only partially blocked by 1265. CXCR4-mediated neuronal apoptosis was c onfirmed in pure populations of rat cerebellar granule neurons and was bloc ked by HA1004, an inhibitor of calcium/calmodulin-dependent: protein kinase EI, protein kinase. A, and protein kinase C. Taken together, these results suggest that progeny HIV-1 virions can influence neuronal signal transduct ion and apoptosis. This process occurs, in part, through CXCR4 and is indep endent of CD4 binding. T-tropic viruses that traffic in and out of the brai n during progressive HIV-1 disease may play an important role in HAD neurop athogenesis.