title: Interleukin-8-mediated heterologous receptor internalization provides resistance to HIV-1 infectivity. Role of signal strength and receptor desensitization.
abstract: Human immunodeficiency virus type 1 (HIV-1) entry into CD4(+) cells requires the chemokine receptors CCR5 or CXCR4 as co-fusion receptors. We have previously demonstrated that chemokine receptors are capable of cross-regulating the functions of each other and, thus, affecting cellular responsiveness at the site of infection. To investigate the effects of chemokine receptor cross-regulation in HIV-1 infection, monocytes and MAGIC5 and rat basophilic leukemia (RBL-2H3) cell lines co-expressing the interleukin-8 (IL-8 or CXCL8) receptor CXCR1 and either CCR5 (ACCR5) or CXCR4 (ACXCR4) were generated. IL-8 activation of CXCR1, but not the IL-8 receptor CXCR2, cross-phosphorylated CCR5 and CXCR4 and cross-desensitized their responsiveness to RANTES (regulated on activation normal T cell expressed and secreted) (CCL5) and stromal derived factor (SDF-1 or CXCL12), respectively. CXCR1 activation internalized CCR5 but not CXCR4 despite cross-phosphorylation of both. IL-8 pretreatment also inhibited CCR5- but not CXCR4-mediated virus entry into MAGIC5 cells. A tail-deleted mutant of CXCR1, DeltaCXCR1, produced greater signals upon activation (Ca(2+) mobilization and phosphoinositide hydrolysis) and cross-internalized CXCR4, inhibiting HIV-1 entry. The protein kinase C inhibitor staurosporine prevented phosphorylation and internalization of the receptors by CXCR1 activation. Taken together, these results indicate that chemokine receptor-mediated HIV-1 cell infection is blocked by receptor internalization but not desensitization alone. Thus, activation of chemokine receptors unrelated to CCR5 and CXCR4 may play a cross-regulatory role in the infection and propagation of HIV-1. Since DeltaCXCR1, but not CXCR1, cross-internalized and cross-inhibited HIV-1 infection to CXCR4, the data indicate the importance of the signal strength of a receptor and, as a consequence, protein kinase C activation in the suppression of HIV-1 infection by cross-receptor-mediated internalization.
authors.affiliation: Department of Biochemistry, Meharry Medical College, 1005 Dr. D.B. Todd Jr. Boulevard, Nashville, TN 37208, USA. mrrichardson@mmc.edu
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Richardson
authors.forename: Kenzo
authors.initials: K
authors.lastname: Tokunaga
authors.forename: Robin
authors.initials: R
authors.lastname: Marjoram
authors.forename: Tetsutaro
authors.initials: T
authors.lastname: Sata
authors.forename: Ralph
authors.initials: R
authors.lastname: Snyderman
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000517:prevention & control; D002118:Calcium / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D016209:Interleukin-8 / Q000502:physiology*; D009000:Monocytes / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D019713:Receptors, CCR5 / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000502:physiology*; D023062:Receptors, Interleukin-8A / Q000502:physiology
chemical_list: D016209:Interleukin-8; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D023062:Receptors, Interleukin-8A; D011493:Protein Kinase C; D002118:Calcium