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Chemokine receptor utilization and macrophage signaling by human immunodeficiency virus type 1 gp120: Implications
Yanjie Yi1, ChuHee Lee, Qing-Hua Liu
1Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Abstract:
Human immunodeficiency virus type 1 (HIV-1) uses the chemokine receptors CCR5 and CXCR4 for entry. Macrophages and microglia (M/M) are the principal productively infected brain cells in HIV encephalopathy (HIVE), and neuronal injury is believed to result both from direct effects of viral proteins and indirect effects mediated by macrophage activation and secretion of neurotoxic products. In vitro, direct injury by the viral envelope glycoprotein gp120 can be mediated by neuronal CXCR4, but most HIV-1 isolates from the central nervous system (CNS) studied to date use CCR5 (R5 strains) rather than CXCR4 (X4 or R5X4 strains). Additionally, it remains unknown how HIV induces M/M activation and neurotoxin secretion. To address these issues, the authors analyzed a CNS-derived primary isolate, TYBE, and showed that it uses CXCR4 only and replicates efficiently in macrophages through CXCR4-mediated entry. The authors also showed that both R5 and X4 gp120 activate intracellular signals in macrophages through CCR5 and CXCR4, including calcium elevations; K+, Cl- and nonselective cation channel activation; phosphorylation of the nonreceptor tyrosine kinase Pyk2; and activation of p38 and SAPK/JNK mitogen-activated protein kinases (MAPKs). Finally, the authors showed that macrophages stimulated with gp120 produce soluble factors through MAPK-dependent pathways, including beta-chemokines implicated in HIVE pathogenesis. The findings emphasize that both X4 and R5 HIV-1 isolates may contribute to HIVE pathogenesis, and that gp120/chemokine receptor interactions in M/M trigger specific signal transduction pathways that may affect M/M function and provide a mechanism underlying CNS injury.
Insights
Human immunodeficiency virus type 1 (HIV-1) entry into brain cells involves chemokine receptors. HIV
Area of Science:
- Neuroscience
- Virology
- Immunology
Background:
- Human immunodeficiency virus type 1 (HIV-1) infects brain cells, leading to HIV encephalopathy (HIVE).
- Macrophages and microglia are key infected cells, with neuronal injury resulting from direct viral effects and indirect inflammatory responses.
- Most HIV-1 strains in the CNS use CCR5, but the mechanisms of macrophage activation and neurotoxin secretion remain unclear.
Purpose of the Study:
- To investigate how HIV-1 activates macrophages and induces neurotoxin secretion.
- To analyze the signaling pathways involved in HIV-1 gp120 interactions with chemokine receptors in macrophages.
- To determine the role of both R5 and X4 HIV-1 strains in HIVE pathogenesis.
Main Methods:
- Analysis of a CXCR4-using CNS-derived HIV-1 isolate (TYBE).
- Assessment of gp120-induced intracellular signaling in macrophages, including calcium, ion channel activity, Pyk2 phosphorylation, and MAPK activation.
- Detection of soluble factors, such as beta-chemokines, produced by gp120-stimulated macrophages.
Main Results:
- The TYBE isolate efficiently replicates in macrophages via CXCR4-mediated entry.
- Both R5 and X4 gp120 activate macrophages through CCR5 and CXCR4, triggering specific intracellular signaling cascades.
- gp120 stimulation leads to MAPK-dependent production of beta-chemokines implicated in HIVE.
Conclusions:
- Both X4 and R5 HIV-1 strains can contribute to HIVE pathogenesis.
- gp120 interaction with chemokine receptors on macrophages initiates signaling pathways that influence macrophage function and contribute to CNS injury.
- Understanding these pathways offers potential targets for therapeutic intervention in HIVE.
