Journal of NeuroVirology

, Volume 10, Supplement 1, pp 91–96

Chemokine receptor utilization and macrophage signaling by human immunodeficiency virus type 1 gp120: Implications for neuropathogenesis

  • Yanjie Yi
  • ChuHee Lee
  • Qing-Hua Liu
  • Bruce D. Freedman
  • Ronald G. Collman
Article

DOI: 10.1080/753312758

Cite this article as:
Yi, Y., Lee, C., Liu, Q. et al. Journal of NeuroVirology (2004) 10: 91. doi:10.1080/753312758

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+, Cland 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 β-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.

Keywords

AIDS dementiaCCR5CXCR4HIV encephalopathymicrogliasignal transductiontropism

Copyright information

© Journal of NeuroVirology, Inc. 2004

Authors and Affiliations

  • Yanjie Yi
    • 1
  • ChuHee Lee
    • 1
  • Qing-Hua Liu
    • 2
  • Bruce D. Freedman
    • 2
  • Ronald G. Collman
    • 1
  1. 1.Department of MedicineUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  2. 2.Department of PathobiologyUniversity of Pennsylvania School of Veterinary MedicinePhiladelphiaUSA