Human immunodeficiency virus type 1–infected monocytic cells can destroy human neural cells after cell‐to‐cell adhesion

Abstract

Primary cultures of human embryonic neurons and astrocytes have been used to test the interactions between neural cells and either human immunodeficiency virus type 1 (HIV-1) or HIV-1-infected monocytes. After direct infection with HIV-1, neither morphological alteration of neurons and astrocytes nor signs of viral replication were observed. Similarly, cultured human neurons and astrocytes were resistant to incubation with the supernatant of HIV-1-infected U937 cells, a human monoblastoid cell line. In contrast, HIV-1-infected U937 monocytic cells adhered to neural cells and induced large plaques of necrosis surrounding them. This cytopathic effect began at the time of viral replication (day 16 after infection). Its intensity depended on that of viral replication, and its range was identical to the region of diffusion of viral antigens, as judged by immunocytochemistry. The cytopathic effect was not dependent on the release of free radicals. It could not be induced by cytokines or cytokine-stimulated U937 cells. It is likely that this cytopathic effect depends on the release of viral antigens either within the site of adherence itself or within close range of the astrocyte membrane.

Cell death in HIV dementia

“…16,50,51 Although neurons are rarely, if ever, infected with HIV, neurons can be exposed to Tat following active release from HIV-infected lymphoid cells and glial cells. [52][53][54] In addition to the direct effect of Tat on neurons, Tat perturbs glial and monocyte/macrophage function, promoting the release of neurotoxic agents including matrix metalloproteinases (MMPs), IL-6, IL-8, RANTES, MCP-1 and TNF-a. [55][56][57][58][59] Although the exact role of these agents in Tat-mediated neurotoxicity remains to be determined, Tat-induced TNF-a release has been implicated in neurotoxicity and MCP-1 levels in CSF have been shown to correlate with the severity of dementia in patients with HIV encephalitis.…”

HIV-1 Trans Activator of Transcription Protein Elicits Mitochondrial Hyperpolarization and Respiratory Deficit, with Dysregulation of Complex IV and Nicotinamide Adenine Dinucleotide Homeostasis in Cortical Neurons

“…These effects may be mediated either at the cell surface, or following intracellular uptake of Tat via its arginine-rich basic domain (8,9). Acute neurotoxic effects of Tat may therefore occur through several mechanisms, including overactivation of N-methyl-D-asparate (NMDA) receptors to cause excitotoxicity and apoptosis (10 -15).…”

HIV-1 Transactivator of Transcription Protein Induces Mitochondrial Hyperpolarization and Synaptic Stress Leading to Apoptosis

“…Tat has been detected in the brain of patients with HIV-1-associated dementia (HAD) by immunoblot analysis (1), and is unique among nonEnvelope proteins in that it is actively secreted by infected glial cells (2), thus increasing the probability that it will be found at higher concentrations in the extracellular space in brain parenchyma relative to other HIV gene products.…”

“…After the 15-min incubation, trypsin was removed, cells were washed twice with HBSS (with Ca ϩ /Mg ϩ ), then dissociated in growth medium (below) by Pasteur pipette trituration by 8-10 passages through a 0.9-mm bore 1000-l blue pipette tip. Dissociated cells were counted by trypan blue viability assay and plated in cell culture plates at 0.5-0.6 ϫ 10 5 cells/cm 2 , on poly(D-lysine)-coated cell culture plastic. The plating and maintenance medium used consisted of Neurobasal with B27 supplement (Invitrogen Life Technologies), as described by Brewer et al (14), and as modified for antioxidant-free culture (14,15).…”