CCR5 levels and expression pattern correlate with infectability by macrophage-tropic HIV-1, in vitro.
Chemokine receptors serve as coreceptors for HIV entry into CD4+ cells. Their expression is thought to determine the tropism of viral strains for different cell types, and also to influence susceptibility to infection and rates of disease progression. Of the chemokine receptors, CCR5 is the most important for viral transmission, since CCR5 is the principal receptor for primary, macrophage-tropic viruses, and individuals homozygous for a defective CCR5 allele (delta32/delta32) are highly resistant to infection with HIV-1. In this study, CCR5-specific mAbs were generated using transfectants expressing high levels of CCR5. The specificity of these mAbs was confirmed using a broad panel of chemokine receptor transfectants, and by their non-reactivity with T cells from delta32/delta32 individuals. CCR5 showed a distinct pattern of expression, being abundant on long-term activated, IL-2-stimulated T cells, on a subset of effector/memory T cells in blood, and on tissue macrophages. A comparison of normal and CCR5 delta32 heterozygotes revealed markedly reduced expression of CCR5 on T cells from the heterozygotes. There was considerable individual to individual variability in the expression of CCR5 on blood T cells, that related to factors other than CCR5 genotype. Low expression of CCR5 correlated with the reduced infectability of T cells with macrophage-tropic HIV-1, in vitro. Anti-CCR5 mAbs inhibited the infection of PBMC by macrophage-tropic HIV-1 in vitro, but did not inhibit infection by T cell-tropic virus. Anti-CCR5 mAbs were poor inhibitors of chemokine binding, indicating that HIV-1 and ligands bind to separate, but overlapping regions of CCR5. These results illustrate many of the important biological features of CCR5, and demonstrate the feasibility of blocking macrophage-tropic HIV-1 entry into cells with an anti-CCR5 reagent.
Wu
L
L
LeukoSite, Inc., Cambridge, Massachusetts 02142, USA.
Paxton
W A
WA
Kassam
N
N
Ruffing
N
N
Rottman
J B
JB
Sullivan
N
N
Choe
H
H
Sodroski
J
J
Newman
W
W
Koup
R A
RA
Mackay
C R
CR
D000483:Alleles; D000911:Antibodies, Monoclonal / Q000276:immunology; D002478:Cells, Cultured; D015658:HIV Infections / Q000235:genetics; D015497:HIV-1 / Q000254:growth & development*; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008264:Macrophages / Q000382:microbiology*; D019713:Receptors, CCR5; D018121:Receptors, Cytokine / Q000378:metabolism*; D015728:Receptors, HIV / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D019713:Receptors, CCR5; D018121:Receptors, Cytokine; D015728:Receptors, HIV