EXPRESSION OF CCR5 INCREASES DURING MONOCYTE DIFFERENTIATION AND DIRECTLY MEDIATES MACROPHAGE SUSCEPTIBILITY TO INFECTION BY HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1

The stage of differentiation and the lineage of CD4(+) cells profoundl y affect their susceptibility to infection by human immunodeficiency v irus type 1 (HIV-1), While CD4(+) T lymphocytes in patients are readil y susceptible to HIV-1 infection, peripheral blood monocytes are relat ively resistant during acute or early infection, even though monocytes also express CD-l and viral strains with macrophage Chl)-tropic pheno types predominate. CCR5, the main coreceptor for hi-tropic viruses, cl early contributes to the ability of CD4(+) T cells to be infected. To determine whether low levels of CCR5 expression account for the block in infection of monocytes, we examined primary monocyte lineage cells during differentiation. Culturing of blood monocytes for 5 days led to an increase in the mean number of CCR5-positive cells from <20% of mo nocytes to >80% of monocyte-derived macrophages (MDM). Levels of CCR5 expression per monocyte were generally low er than those on MDM, perha ps below a minimum threshold level necessary for efficient infection. Productive infection may be restricted to the small subset of monocyte s that express relatively high levels of CCR5. Steady-state CCR5 mRNA levels also increased four-to fivefold during MDM differentiation. Inf ection of MDM by hi-tropic HIV-1(JRFL) resulted in > 10-fold-higher le vels of p24, and MDM harbored >30-fold more HIV-1 DNA copies than mono cytes. In the presence of the CCR5-specific monoclonal antibody (MAb) 2D7, virus production and cellular levels of HIV DNA were decreased by >80% in MDM, indicating a block in viral entry. There was a direct as sociation between levels of CCR5 and differentiation of monocytes to m acrophages. Levels of CCR5 were related to monocyte resistance and mac rophage susceptibility to infection because infection by the M-tropic strain HIV-1(JRFL) could be blocked by MAb 2D7. These results provide direct evidence that CCR5 functions as a coreceptor for HIV-1 infectio n of primary macrophages.