title: Role of CCR5 in infection of primary macrophages and lymphocytes by macrophage-tropic strains of human immunodeficiency virus: resistance to patient-derived and prototype isolates resulting from the delta ccr5 mutation.
abstract: The alpha-chemokine receptor fusin (CXCR-4) and beta-chemokine receptor CCR5 serve as entry cofactors for T-cell (T)-tropic and macrophage (M)-tropic human immunodeficiency virus type 1 (HIV-1) strains, respectively, when expressed with CD4 in otherwise nonpermissive cells. Some M-tropic and dual-tropic strains can also utilize other beta-chemokine receptors, such as CCR2b and CCR3. A mutation of CCR5 (delta ccr5) was recently found to be common in certain populations and appears to confer protection against HIV-1 in vivo. Here, we show that this mutation results in a protein that is expressed intracellularly but not on the cell surface. Primary CD4 T cells from delta ccr5 homozygous individuals were highly resistant to infection with prototype M-tropic HIV-1 strains, including an isolate (YU-2) that uses CCR5 and CCR3, but were permissive for both a T-tropic strain (3B) and a dual-tropic variant (89.6) that uses CXCR-4, CCR5, CCR3, or CCR2b. These cells were also resistant to M-tropic patient isolates but were readily infected by T-tropic patient isolates. Primary macrophages from delta ccr5 homozygous individuals were also resistant to infection with M-tropic strains, including YU-2, but the dual-tropic strain 89.6 was able to replicate in them even though macrophages are highly resistant to CXCR-4-dependent T-tropic isolates. These data show that CCR5 is the essential cofactor for infection of both primary macrophages and T lymphocytes by most M-tropic strains of HIV-1. They also suggest that CCR3 does not function for HIV-1 entry in primary lymphocytes or macrophages, but that a molecule(s) other than CCR5 can support entry into macrophages by certain virus isolates. These studies further define the cellular basis for the resistance to HIV-1 infection of individuals lacking functional CCR5.
authors.affiliation: Division of Pulmonary and Critical Care, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
authors.forename: S
authors.initials: S
authors.lastname: Rana
authors.forename: G
authors.initials: G
authors.lastname: Besson
authors.forename: D G
authors.initials: DG
authors.lastname: Cook
authors.forename: J
authors.initials: J
authors.lastname: Rucker
authors.forename: R J
authors.initials: RJ
authors.lastname: Smyth
authors.forename: Y
authors.initials: Y
authors.lastname: Yi
authors.forename: J D
authors.initials: JD
authors.lastname: Turner
authors.forename: H H
authors.initials: HH
authors.lastname: Guo
authors.forename: J G
authors.initials: JG
authors.lastname: Du
authors.forename: S C
authors.initials: SC
authors.lastname: Peiper
authors.forename: E
authors.initials: E
authors.lastname: Lavi
authors.forename: M
authors.initials: M
authors.lastname: Samson
authors.forename: F
authors.initials: F
authors.lastname: Libert
authors.forename: C
authors.initials: C
authors.lastname: Liesnard
authors.forename: G
authors.initials: G
authors.lastname: Vassart
authors.forename: R W
authors.initials: RW
authors.lastname: Doms
authors.forename: M
authors.initials: M
authors.lastname: Parmentier
authors.forename: R G
authors.initials: RG
authors.lastname: Collman
mesh_terms: D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D002478:Cells, Cultured; D015497:HIV-1 / Q000276:immunology / Q000502:physiology*; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000821:virology*; D008264:Macrophages / Q000166:cytology / Q000821:virology*; D016296:Mutagenesis; D054397:Receptors, CCR3; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015728:Receptors, HIV / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D013045:Species Specificity; D014779:Virus Replication
chemical_list: C515350:CCR3 protein, human; D015704:CD4 Antigens; D016827:CD8 Antigens; D054397:Receptors, CCR3; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D015728:Receptors, HIV