Study of Receptor-Mediated Neurotoxins Released by HIV-1-Infected Mononuclear Phagocytes Found in Human Brain

Abstract

Although there is growing evidence that neurotoxic molecules produced by HIV-1-infected mononuclear phagocytes damage neurons, the precise mechanisms of neuronal attack remain uncertain. One class of cytotoxin involves neuronal injury mediated via the NMDA receptor. We examined blood monocytes and brain mononuclear cells isolated at autopsy from HIV-1-infected individuals for the ability to release NMDA-like neuron-killing factors. We found that a neurotoxic amine, NTox, was produced by blood monocytes and by brain mononuclear phagocytes infected with retrovirus. In vivo injections of minute quantities of NTox produced selective damage to hippocampal pyramidal neurons. NTox can be extracted directly from brain tissues infected with HIV-1 and showed structural features similar to wasp and spider venoms. In contrast to NTox, HIV-1 infection did not increase the release of the NMDA excitotoxin quinolinic acid (QUIN) from mononuclear cells. Although we found modest elevations of QUIN in the CSF of HIV-1-infected individuals, the increases were likely attributable to entry through damaged blood-brain barrier. Taken together, our data pinpoint NTox, rather than QUIN, as a major NMDA receptor-directed toxin associated with neuro-AIDS.

HIV-1 infection and AIDS: consequences for the central nervous system

“…44,45 In contrast, increased numbers of microglia, 44 elevated TNF-a mRNA in microglia and astrocytes, 46 evidence of excitotoxins, [47][48][49] decreased synaptic and dendritic density, 45,50 and selective neuronal loss 51,52 constitute the pathologic features most closely associated with the clinical signs of HAD. Furthermore, signs of neuronal apoptosis have been linked to HAD, [53][54][55] although this finding is not clearly associated with viral burden 53 or a history of dementia.…”

Response of Cell Cycle Proteins to Neurotrophic Factor and Chemokine Stimulation in Human Neuroglia

“…In HIVE these factors are secreted by infected/activated macrophages (17,20,21,34,35,46,47) and associated with neuronal loss. It has been proposed that neuronal loss in HIVE may be due to increased secretion of NTF like BDNF (55) and chemokines like MCP1 or RANTES (10,24,39,52), yet how these factors may lead to neuronal death is not clear.…”

Antiretroviral Therapy and HIV-Associated Neurocognitive Disorders

“…A small number of neurons and glia may also become infected; however, such infection is not productive (Gendelman, Lipton et al 1994;Kaul, Zheng et al 2005). Two major mechanisms of neuronal damage have been proposed: 1) Direct neurotoxicity by viral proteins such as HIV envelope glycoprotein (gp120) and HIV transactivator of transcription (Tat) protein, and, 2) Indirect neurotoxicity induced by soluble factors released by infected and/or activated macrophages including, but not limited to, quinolinic acid, TNF-, reactive oxygen species (ROS), and cytokines such as CXCL12 (stromal cell-derived factor-1, SDF-1), CCL2 (monocyte chemotactic protein-1, MCP-1), and interleukin-6 (IL-6) (Price, Brew et al 1988;Giulian, Yu et al 1996;Soontornniyomkij, Nieto-Rodriguez et al 1998;Lindl, Marks et al 2010). Most of these factors not only directly affect neurons but also induce the secretion of more of these and other neurotoxic soluble factors, such as excitatory amino acids such as glutamate from neighboring macrophages/microglia, and astrocytes (Gorry, Ong et al 2003;.…”