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.
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