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(+) cel ls. Their expression is thought to determine the tropism of viral stra ins 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 indivi duals homozygous for a defective CCR5 allele (Delta 32/Delta 32) are h ighly 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 c hemokine receptor transfectants, and by their non-reactivity with T ce lls from Delta 32/Delta 32 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 tiss ue macrophages. A comparison of normal and CCR5 Delta 32 heterozygotes revealed markedly reduced expression of CCR5 on T cells from the hete rozygotes. There was considerable individual to individual variability in the expression of CCR5 on blood T cells, that related to factors o ther than CCR5 genotype. Low expression of CCR5 correlated with the re duced infectability of T cells with macrophage-tropic HIV-1, in vitro. Anti-CCR5 mAbs inhibited the infection of PBMC by macrophage-tropic H IV-1 in vitro, but did not inhibit infection by T cell-tropic virus. A nti-CCR5 mAbs were poor inhibitors of chemokine binding, indicating th at HIV-1 and ligands bind to separate, but overlapping regions of CCR5 . These results illustrate many of the important biological features o f CCR5, and demonstrate the feasibility of blocking macrophage-tropic HIV-1 entry into cells with an anti-CCR5 reagent.