title: CD4-independent infection of astrocytes by human immunodeficiency virus type 1: requirement for the human mannose receptor.
abstract: Human immunodeficiency virus type 1 (HIV-1) infection occurs in the central nervous system and causes a variety of neurobehavioral and neuropathological disorders. Both microglia, the residential macrophages in the brain, and astrocytes are susceptible to HIV-1 infection. Unlike microglia that express and utilize CD4 and chemokine coreceptors CCR5 and CCR3 for HIV-1 infection, astrocytes fail to express CD4. Astrocytes express several chemokine coreceptors; however, the involvement of these receptors in astrocyte HIV-1 infection appears to be insignificant. In the present study using an expression cloning strategy, the cDNA for the human mannose receptor (hMR) was found to be essential for CD4-independent HIV-1 infectivity. Ectopic expression of functional hMR rendered U87.MG astrocytic cells susceptible to HIV-1 infection, whereas anti-hMR serum and hMR-specific siRNA blocked HIV-1 infection in human primary astrocytes. In agreement with these findings, hMR bound to HIV-1 virions via the abundant and highly mannosylated sugar moieties of HIV-1 envelope glycoprotein gp120 in a Ca(2+)-dependent fashion. Moreover, hMR-mediated HIV-1 infection was dependent upon endocytic trafficking as assessed by transmission electron microscopy, as well as inhibition of viral entry by endosomo- and lysosomotropic drugs. Taken together, these results demonstrate the direct involvement of hMR in HIV-1 infection of astrocytes and suggest that HIV-1 interaction with hMR plays an important role in HIV-1 neuropathogenesis.
authors.affiliation: Department of Microbiology and Immunology and Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Byung Oh
authors.initials: BO
authors.lastname: Kim
authors.forename: Vincent H
authors.initials: VH
authors.lastname: Gattone
authors.forename: Jinliang
authors.initials: J
authors.lastname: Li
authors.forename: Avindra
authors.initials: A
authors.lastname: Nath
authors.forename: Janice
authors.initials: J
authors.lastname: Blum
authors.forename: Johnny J
authors.initials: JJ
authors.lastname: He
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology* / Q000648:ultrastructure / Q000821:virology*; D015704:CD4 Antigens / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D004705:Endocytosis; D015658:HIV Infections / Q000209:etiology / Q000503:physiopathology / Q000821:virology; D015497:HIV-1 / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D037181:Lectins, C-Type / Q000502:physiology*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000502:physiology*; D051379:Mice; D008854:Microscopy, Electron; D041681:NIH 3T3 Cells; D019713:Receptors, CCR5 / Q000502:physiology; D019718:Receptors, CXCR4 / Q000502:physiology; D011956:Receptors, Cell Surface / Q000502:physiology*; D015728:Receptors, HIV / Q000502:physiology; D014774:Virulence
chemical_list: D015704:CD4 Antigens; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D011956:Receptors, Cell Surface; D015728:Receptors, HIV