Regions in beta-chemokine receptors CCR5 and CCR2b that determine HIV-1 cofactor specificity.
Macrophage-tropic (M-tropic) HIV-1 strains use the beta-chemokine receptor CCR5, but not CCR2b, as a cofactor for membrane fusion and infection, while the dual-tropic strain 89.6 uses both. CCR5/2b chimeras and mutants were used to map regions of CCR5 important for cofactor function and specificity. M-tropic strains required either the amino-terminal domain or the first extracellular loop of CCR5. A CCR2b chimera containing the first 20 N-terminal residues of CCR5 supported M-tropic envelope protein fusion. Amino-terminal truncations of CCR5/CCR2b chimeras indicated that residues 2-5 are important for M-tropic viruses, while 89.6 is dependent on residues 6-9. The identification of multiple functionally important regions in CCR5, coupled with differences in how CCR5 is used by M- and dual-tropic viruses, suggests that interactions between HIV-1 and entry cofactors are conformationally complex.
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia 19104, USA.
J
J
Rucker
M
M
Samson
B J
BJ
Doranz
F
F
Libert
J F
JF
Berson
Y
Y
Yi
R J
RJ
Smyth
R G
RG
Collman
C C
CC
Broder
G
G
Vassart
R W
RW
Doms
M
M
Parmentier
D000595:Amino Acid Sequence; D015704:CD4 Antigens / Q000502:physiology; D003588:Cytopathogenic Effect, Viral; D006031:Glycosylation; D015497:HIV-1 / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D046911:Macromolecular Substances; D008264:Macrophages / Q000821:virology; D008561:Membrane Fusion; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000737:chemistry* / Q000502:physiology; D015728:Receptors, HIV / Q000737:chemistry* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D017384:Sequence Deletion; D013329:Structure-Activity Relationship
C515334:CCR2 protein, human; D015704:CD4 Antigens; D046911:Macromolecular Substances; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D015728:Receptors, HIV; D011993:Recombinant Fusion Proteins