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Published on: August 31, 2014
A CXCR1 haplotype hampers HIV-1 matrix protein p17 biological activity
Cinzia Giagulli1, Francesca Caccuri, Francesca Cignarella
1aSection 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.
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.
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-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.
Insights
HIV matrix protein p17 promotes monocyte inflammation via CXCR1. Genetic variations in CXCR1 (CXCR1_300_142) block p17
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- Monocyte inflammatory processes are key in AIDS pathogenesis.
- HIV-1 matrix protein p17 exhibits IL-8-like activity on monocytes via CXCR1.
- A CXCR1 gene haplotype (CXCR1_300_142) is linked to slower HIV progression.
Purpose of the Study:
- To investigate how CXCR1 genetic variations affect p17's biological activity.
- To understand the molecular mechanisms behind p17-CXCR1 interactions in different genetic contexts.
Main Methods:
- Utilized Jurkat cell lines overexpressing wild-type and variant CXCR1 receptors.
- Employed surface plasmon resonance (SPR) and multispectral imaging flow cytometry.
- Conducted mutagenesis studies to analyze receptor activation pathways.
Main Results:
- Jurkat cells with CXCR1_300_142 and monocytes from individuals with this haplotype showed reduced migration in response to p17.
- p17 bound to both CXCR1 and CXCR1_300_142 with similar affinity.
- p17 activated wild-type CXCR1 but not CXCR1_300_142, failing to phosphorylate ERK1/2.
Conclusions:
- The inability of p17 to activate the CXCR1_300_142 variant suggests a role for p17 in AIDS pathogenesis.
- Blocking the p17/CXCR1 interaction may offer a therapeutic strategy for HIV infection.
