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

Giagulli, Cinzia, Caccuri, Francesca, Cignarella, Francesca, Lougaris, Vassilios, Martorelli, Debora, Bugatti, Antonella, Rusnati, Marco, Dolcetti, Riccardo, Vitali, Massimiliano, Plebani, Alessandro, Fiorentini, Simona and Caruso, Arnaldo (2014) A CXCR1 haplotype hampers HIV-1 matrix protein p17 biological activity. AIDS, 28 16: 2355-2364. doi:10.1097/QAD.0000000000000423

Author Giagulli, Cinzia
Caccuri, Francesca
Cignarella, Francesca
Lougaris, Vassilios
Martorelli, Debora
Bugatti, Antonella
Rusnati, Marco
Dolcetti, Riccardo
Vitali, Massimiliano
Plebani, Alessandro
Fiorentini, Simona
Caruso, Arnaldo
Title A CXCR1 haplotype hampers HIV-1 matrix protein p17 biological activity
Journal name AIDS   Check publisher's open access policy
ISSN 1473-5571
Publication date 2014-10-23
Year available 2014
Sub-type Article (original research)
DOI 10.1097/QAD.0000000000000423
Open Access Status Not yet assessed
Volume 28
Issue 16
Start page 2355
End page 2364
Total pages 10
Place of publication Philadelphia, PA, United States
Publisher Lippincott Williams & Wilkins
Language eng
Formatted abstract
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. 

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.
Keyword Adhesion
Glu-Leu-Arg motif
HIV-1 matrix protein p17
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 3 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 3 times in Scopus Article | Citations
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