title: A CXCR1 haplotype hampers HIV-1 matrix protein p17 biological activity.
abstract: OBJECTIVE
  Monocyte inflammatory processes are fundamental events in AIDS pathogenesis. HIV-1 matrix protein p17, 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.
  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-Arg-like 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.
authors.affiliation: aSection of Microbiology, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Brescia bPediatrics Clinic and Institute for Molecular Medicine 'A. Nocivelli', Department of Clinical and Experimental Sciences, University of Brescia, Brescia cCancer Bio-Immunotherapy Unit, CRO-IRCCS, National Cancer Institute, Aviano (PN) dSection of Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Brescia, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giagulli
authors.forename: Francesca
authors.initials: F
authors.lastname: Caccuri
authors.forename: Francesca
authors.initials: F
authors.lastname: Cignarella
authors.forename: Vassilios
authors.initials: V
authors.lastname: Lougaris
authors.forename: Debora
authors.initials: D
authors.lastname: Martorelli
authors.forename: Antonella
authors.initials: A
authors.lastname: Bugatti
authors.forename: Marco
authors.initials: M
authors.lastname: Rusnati
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dolcetti
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Vitali
authors.forename: Alessandro
authors.initials: A
authors.lastname: Plebani
authors.forename: Simona
authors.initials: S
authors.lastname: Fiorentini
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Caruso
mesh_terms: D002465:Cell Movement; D005434:Flow Cytometry; D015488:HIV Antigens / Q000378:metabolism* / Q000502:physiology*; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D006239:Haplotypes; D054884:Host-Pathogen Interactions; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D019169:Jurkat Cells; D011485:Protein Binding; D023062:Receptors, Interleukin-8A / Q000235:genetics* / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000378:metabolism* / Q000502:physiology*
chemical_list: D015488:HIV Antigens; D016209:Interleukin-8; D023062:Receptors, Interleukin-8A; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1