Down-regulation of CXCR-4 and CCR-5 expression by interferon-gamma is associated with inhibition of chemotaxis and human immunodeficiency virus (HIV) replication but not HIV entry into human monocytes.
Alterations in the expression of CXCR4 and CCR5, the co-receptors for HIV entry, may be associated with susceptibility of monocytic cells to HIV infection. Interferon (IFN)-gamma has been shown to inhibit HIV replication in monocytic cells, but the molecular mechanism involved is not well understood. To determine if IFN-gamma regulates HIV replication by altering CXCR-4/CCR-5 expression and hence virus entry into monocytic cells, we investigated the effects of IFN-gamma on CXCR-4 and CCR-5 expression and its biological implications with respect to HIV entry, replication and chemotaxis towards the CXCR-4 and CCR-5 ligands SDF-1 and MIP-1alpha, respectively. IFN-gamma decreased CXCR-4 and CCR-5 expression on monocytes derived from HIV-negative adults, HIV-positive adults and HIV-negative cord blood. This down-regulation of chemokine receptor expression did not result in a corresponding change in mRNA expression but was associated with elevated levels of the endogenously produced chemokines SDF-1 and RANTES. Furthermore, IFN-gamma inhibited chemotaxis in response to SDF-1 and MIP-1alpha, inhibited HIV replication, but failed to inhibit virus entry in monocytic cells. These results suggest that although IFN-gamma-induced down-regulation of CXCR-4 and CCR-5 expression is associated with an inhibition of SDF-1-/MIP-1alpha-mediated chemotaxis, IFN-gamma-induced inhibition of HIV replication may be mediated at levels subsequent to the virus entry.
Creery
D
D
Department of Pediatrics, Research Institute, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada.
Weiss
W
W
Lim
W T
WT
Aziz
Z
Z
Angel
J B
JB
Kumar
A
A
D000328:Adult; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000276:immunology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000276:immunology; D002633:Chemotaxis / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D006678:HIV / Q000276:immunology / Q000502:physiology*; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D019402:Macrophage Inflammatory Proteins / Q000276:immunology; D009000:Monocytes / Q000276:immunology*; D012333:RNA, Messenger / Q000032:analysis; D019713:Receptors, CCR5 / Q000032:analysis*; D019718:Receptors, CXCR4 / Q000032:analysis*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014158:Transcription, Genetic / Q000276:immunology; D014779:Virus Replication / Q000276:immunology*
C515255:CXCL12 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D007371:Interferon-gamma