A CXCR1 haplotype hampers HIV-1 matrix protein p17 biological activity

Cinzia Giagulli, Francesca Caccuri, Francesca Cignarella, Vassilios Lougaris, Debora Martorelli, Antonella Bugatti, Marco Rusnati, Riccardo Dolcetti, Massimiliano Vitali, Alessandro Plebani, Simona Fiorentini, Arnaldo Caruso

Research output: Contribution to journalArticlepeer-review

Abstract

Design/methods/results: Our results show that Jurkat cells overexpressing CXCR1 or the receptor carrying single polymorphism CXCR1-300 or CXCR1-142 are able to adhere and migrate in response to both IL-8 and p17. On the contrary, Jurkat cells overexpressing CXCR1-300-142 and monocytes of individuals with such CXCR1 polymorphisms lose the capacity to adhere and migrate in response to p17, but not to their physiological ligand IL-8. Surface plasmon resonance (SPR) and multispectral imaging flow cytometry showed that p17 bound with similar affinity to CXCR1 and CXCR1-300-142. Moreover, whereas p17 was able to activate CXCR1, it was incapable of functionally interacting with CXCR1-300-142 by phosphorylating extracellular signal-regulated kinase 1/2, which regulates chemokine-induced cellular responses. Finally, mutagenesis studies showed that, unlike IL-8, p17 does not use Glu-Leu-Arglike motifs to activate CXCR1.

Conclusions: Our results, showing the inability of p17 to activate CXCR1-300-142, a receptor found to be expressed on immune cells of patients with a low progression of HIV disease, point to a crucial role of p17 in AIDS pathogenesis. Our findings herein call for an exploration of the therapeutic potential of blocking the p17/CXCR1 axis in HIV infection.

Objective: Monocyte inflammatory processes are fundamental events in AIDS pathogenesis. HIV-1 matrix protein p1 7, released from infected cells, was found to exert an interleukin (IL)-8 chemokine-like activity on human monocytes, promoting their trafficking and sustaining inflammatory processes, after binding to CXCR1. A haplotype of the CXCR1 gene(CXCR1-300-142) has been associated with slow HIV disease progression. Here, we determine how CXCR1 genetic variations impact on p17 biological activity.

Original languageEnglish
Pages (from-to)2355-2364
Number of pages10
JournalAIDS (London, England)
Volume28
Issue number16
DOIs
Publication statusPublished - 2014

Keywords

  • Adhesion
  • CXCR1
  • CXCR1-300-142
  • Glu-Leu-Arg motif
  • HIV-1 matrix protein p17
  • IL-8
  • Migration

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases
  • Medicine(all)

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