Interleukin-8-mediated Heterologous Receptor Internalization Provides Resistance to HIV-1 Infectivity

Abstract

Chemokines are a diverse gene family of chemotactic cytokines that induce leukocyte accumulation and activation at sites of inflammation (1-3). They also mediate tumor cell trafficking and metastasis and participate in many acute and chronic inflammatory diseases (4, 5). Chemokine functions are mediated via cell surface G-protein-coupled receptors that couple predominantly to G i (1-3, 18, 35). Chemokine receptors, most notably CCR5 and CXCR4, also serve as co-receptors for human immunodeficiency virus type 1 (HIV-1) 1 entry into CD4 ϩ cells (6, 7). To date, the relationship between the activation of these receptors and their role in HIV-1 infection is not well understood.Like many members of the G-protein-coupled receptor family, CCR5 and CXCR4 become desensitized upon agonist exposure, resulting in a loss of cellular responsiveness to agonist followed by a decrease in the number of cell surface receptors (8 -13). Phosphorylations of the carboxyl terminus of the receptors are responsible for the desensitization and down-regulation (8 -13). We have previously shown that chemokine receptors cross-regulate the functions of each other (14, 35). The interleukin-8 (IL-8 or CXCL8) receptor CXCR1 cross-phosphorylated and cross-desensitized CCR1-mediated cellular responses to RANTES (CCL5) (14). The formyl peptide chemoattractant receptor also cross-desensitized CCR5-mediated cellular responses to RANTES in monocytes and diminished the ability of RANTES to mediate HIV-1 entry and infection (15,16).While HIV-1 infection requires the CD4 receptor, the role of a chemokine receptor as the fusion cofactor depends on the target cell (17). Both macrophages and T lymphocytes express CCR5 and CXCR4 (18). Macrophages, however, utilize CCR5 for HIV-1 entry (M-tropism), whereas CD4 ϩ T lymphocytes use CXCR4 (T-tropism) (18). In addition to CCR5 and CXCR4, macrophages and CD4 ϩ T lymphocytes express other chemokine receptors including the IL-8 receptors CXCR1 and CXCR2 (1-8 ϫ 10 6 receptors/cell) (1, 18 -24). In the present study we sought to determine the role of cross-regulation by IL-8 receptors in CCR5-and CXCR4-mediated cellular activation and HIV-1 infection. For this purpose, monocytes and MAGIC5 and RBL-2H3 cells stably expressing different combination of receptors were used to study the mechanisms of cross-regulation among IL-8, CCR5, and CXCR4. The results demonstrate that IL-8 led to the cross-phosphorylation and cross-desensitization of both CCR5 and CXCR4. However, IL-8 down-regulated and

A haplotype of the human CXCR1 gene protective against rapid disease progression in HIV-1+patients

“…HIV-1 replication was shown to be up-regulated by IL-8 in macrophages and T lymphocytes, and inhibited by IL-8 antagonists and GRO-␣ (18). Reduced CXCR1 activity upon HIV-1 infection due to cross-receptor-mediated internalisation with the major coreceptors CCR5 and CXCR4 has been shown (19). These observations suggest that CXCR1 and CXCR2 could affect AIDS-related conditions.…”

Synergy between Coproduced CC and CXC Chemokines in Monocyte Chemotaxis through Receptor-Mediated Events

“…Indeed, CCL7 probably uses the same receptor CCR2 and signal transduction pathways as CCL2 in monocytes, because CCL2 cross-desensitizes the calcium and chemotactic response of CCL7 and vice versa in these cells (Sozzani et al, 1994(Sozzani et al, , 1995. Moreover, CXCL8 activation of CXCR1 cross-phosphorylates CXCR4 and cross-desensitizes the responsiveness of monocytes to CXCL12 (Richardson et al, 2003). This desensitization between chemokine receptors could explain the lack of synergy between CCL7 and CCL2 or between CXCL8 and CXCL12 in monocytic cell migration.…”

An Overall Picture of Chemokine Receptors: Basic Research and Drug Development

“…However, receptor phosphorylation may be the major reason for acute receptor desensitization, in which the C-terminal of the receptor is largely involved. Enhanced signaling after deletion of the Cterminal has been observed in several chemokine receptors [25,65,66]. Regulation of the receptor desensitization by β-arresting also appears highly dependent on the C-terminal of the receptor because receptor desensitization mediated by β-arrestin is not observed in a C-terminal truncated CXCR4 although it still can bind to β-arresin [67].…”

“…However, PKC may account for the hetero-phosphorylation and desensitization but only partially involved in agonist induced homophosphorylation and desensitization. Inhibition of PKC only partially decreases SDF-1-induced CXCR4 phosphorylation [25] but prevents phosphorylation of CXCR4 induced by CXCR1 activation [65]. N-formyl-methionyl-leucylphenylalanine also rapidly induces a PKC-mediated serine phosphorylation of the CCR5 [68].…”