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.
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.
Rana
S
S
Division of Pulmonary and Critical Care, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Besson
G
G
Cook
D G
DG
Rucker
J
J
Smyth
R J
RJ
Yi
Y
Y
Turner
J D
JD
Guo
H H
HH
Du
J G
JG
Peiper
S C
SC
Lavi
E
E
Samson
M
M
Libert
F
F
Liesnard
C
C
Vassart
G
G
Doms
R W
RW
Parmentier
M
M
Collman
R G
RG
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
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