A CCR5/CXCR4-independent coreceptor pathway on human macrophages supports efficient SIV env-mediated fusion but not infection: implications for alternative pathways of viral entry.
Several coreceptors in addition to CCR5 and CXCR4 support immunodeficiency virus entry in transfected cells, but whether they could play a role in HIV-1 pathogenesis is uncertain. To probe whether human macrophages express potentially functional alternative entry pathways, we analyzed cell-cell fusion and infection of primary macrophage by several SIVmac Envs. All Envs fused with normal macrophages. One, SIVmac316, also fused efficiently with macrophages lacking CCR5. CCR5-independent fusion was not mediated by CXCR4 and was CD4 dependent, while CCR5-mediated fusion was partly independent of CD4. However, pseudotype virions carrying the SIVmac316 Env and HIV-1 core could not infect macrophages through the CCR5-independent pathway, although they did infect wild-type macrophages. Thus, human macrophages possess an alternative coreceptor pathway that mediates SIV Env fusion but does not support infection. Macrophage entry pathways other than CCR5 and CXCR4 may have limited potential in pathogenesis given their restricted capacity for infection despite efficient fusion.
Yi
Y
Y
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Singh
A
A
Isaacs
S N
SN
Collman
R G
RG
D017931:DNA Primers; D015686:Gene Products, env / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000821:virology*; D019713:Receptors, CCR5 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015302:Simian Immunodeficiency Virus / Q000472:pathogenicity*; D014760:Viral Fusion Proteins / Q000378:metabolism*; D014771:Virion
D017931:DNA Primers; D015686:Gene Products, env; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D015682:Retroviridae Proteins, Oncogenic; D014760:Viral Fusion Proteins; C059580:transmembrane protein, Simian immunodeficiency virus