Coreceptor competition for association with CD4 may change the susceptibility of human cells to infection with T-tropic and macrophagetropic isolatesof human immunodeficiency virus type 1

The chemokine receptors CCR5 and CXCR4 were found to function in vivo as th e principal coreceptors for hi-tropic and T-tropic human immunodeficiency v irus (HIV) strains, respectively. Since many primary cells express multiple chemokine receptors, it mas important to determine if the efficiency of vi rus-cell fusion is influenced not only by the presence of the appropriate c oreceptor (CXCR4 or CCR5) but also by the levels of other coreceptors expre ssed by the same target cells, We found that in cells with low to medium su rface CD4 density, coexpression of CCR5 and CXCR4 resulted in a significant reduction in the fusion with CXCR4 domain (X4) envelope-expressing cells a nd in their susceptibility to infection with X4 viruses. The inhibition cou ld be reversed either by increasing the density of surface CD4 or by antibo dies against the N terminus and second extracellular domains of CCRS, In ad dition, treatment of macrophages with a combination of anti-CCR5 antibodies or beta-chemokines increased their fusion with X4 envelope-expressing cell s, Conversely, overexpression of CXCR4 compared with CCR5 inhibited CCR5-de pendent HIV-dependent fusion in 3T3.CD4.401 cells, Thus, coreceptor competi tion for association with CD4 may occur in vivo and is likely to have impor tant implications for the course of HIV type 1 infection, as well as for th e outcome of coreceptor-targeted therapies.