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Interleukin-8-mediated heterologous receptor internalization provides resistance to HIV-1 infectivity. Role of signal strength and receptor desensitization.

Publication ,  Journal Article
Richardson, RM; Tokunaga, K; Marjoram, R; Sata, T; Snyderman, R
Published in: J Biol Chem
May 2, 2003

Human immunodeficiency virus type 1 (HIV-1) entry into CD4(+) cells requires the chemokine receptors CCR5 or CXCR4 as co-fusion receptors. We have previously demonstrated that chemokine receptors are capable of cross-regulating the functions of each other and, thus, affecting cellular responsiveness at the site of infection. To investigate the effects of chemokine receptor cross-regulation in HIV-1 infection, monocytes and MAGIC5 and rat basophilic leukemia (RBL-2H3) cell lines co-expressing the interleukin-8 (IL-8 or CXCL8) receptor CXCR1 and either CCR5 (ACCR5) or CXCR4 (ACXCR4) were generated. IL-8 activation of CXCR1, but not the IL-8 receptor CXCR2, cross-phosphorylated CCR5 and CXCR4 and cross-desensitized their responsiveness to RANTES (regulated on activation normal T cell expressed and secreted) (CCL5) and stromal derived factor (SDF-1 or CXCL12), respectively. CXCR1 activation internalized CCR5 but not CXCR4 despite cross-phosphorylation of both. IL-8 pretreatment also inhibited CCR5- but not CXCR4-mediated virus entry into MAGIC5 cells. A tail-deleted mutant of CXCR1, DeltaCXCR1, produced greater signals upon activation (Ca(2+) mobilization and phosphoinositide hydrolysis) and cross-internalized CXCR4, inhibiting HIV-1 entry. The protein kinase C inhibitor staurosporine prevented phosphorylation and internalization of the receptors by CXCR1 activation. Taken together, these results indicate that chemokine receptor-mediated HIV-1 cell infection is blocked by receptor internalization but not desensitization alone. Thus, activation of chemokine receptors unrelated to CCR5 and CXCR4 may play a cross-regulatory role in the infection and propagation of HIV-1. Since DeltaCXCR1, but not CXCR1, cross-internalized and cross-inhibited HIV-1 infection to CXCR4, the data indicate the importance of the signal strength of a receptor and, as a consequence, protein kinase C activation in the suppression of HIV-1 infection by cross-receptor-mediated internalization.

Duke Scholars

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

May 2, 2003

Volume

278

Issue

18

Start / End Page

15867 / 15873

Location

United States

Related Subject Headings

  • Receptors, Interleukin-8A
  • Receptors, CXCR4
  • Receptors, CCR5
  • Protein Kinase C
  • Phosphorylation
  • Monocytes
  • Interleukin-8
  • Humans
  • HIV-1
  • Calcium
 

Citation

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Richardson, R. M., Tokunaga, K., Marjoram, R., Sata, T., & Snyderman, R. (2003). Interleukin-8-mediated heterologous receptor internalization provides resistance to HIV-1 infectivity. Role of signal strength and receptor desensitization. J Biol Chem, 278(18), 15867–15873. https://doi.org/10.1074/jbc.M211745200
Richardson, Ricardo M., Kenzo Tokunaga, Robin Marjoram, Tetsutaro Sata, and Ralph Snyderman. “Interleukin-8-mediated heterologous receptor internalization provides resistance to HIV-1 infectivity. Role of signal strength and receptor desensitization.J Biol Chem 278, no. 18 (May 2, 2003): 15867–73. https://doi.org/10.1074/jbc.M211745200.
Richardson RM, Tokunaga K, Marjoram R, Sata T, Snyderman R. Interleukin-8-mediated heterologous receptor internalization provides resistance to HIV-1 infectivity. Role of signal strength and receptor desensitization. J Biol Chem. 2003 May 2;278(18):15867–73.
Richardson, Ricardo M., et al. “Interleukin-8-mediated heterologous receptor internalization provides resistance to HIV-1 infectivity. Role of signal strength and receptor desensitization.J Biol Chem, vol. 278, no. 18, May 2003, pp. 15867–73. Pubmed, doi:10.1074/jbc.M211745200.
Richardson RM, Tokunaga K, Marjoram R, Sata T, Snyderman R. Interleukin-8-mediated heterologous receptor internalization provides resistance to HIV-1 infectivity. Role of signal strength and receptor desensitization. J Biol Chem. 2003 May 2;278(18):15867–15873.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

May 2, 2003

Volume

278

Issue

18

Start / End Page

15867 / 15873

Location

United States

Related Subject Headings

  • Receptors, Interleukin-8A
  • Receptors, CXCR4
  • Receptors, CCR5
  • Protein Kinase C
  • Phosphorylation
  • Monocytes
  • Interleukin-8
  • Humans
  • HIV-1
  • Calcium