Bone marrow CD34(+) cells and megakaryoblasts secrete beta-chemokines thatblock infection of hematopoietic cells by M-tropic R5 HIV

CD34(+) cells are nonpermissive to infection by HIV strains X4 and R5, desp ite the fact that many CD34(+) cells express high levels of the viral recep tor protein CD4 and the coreceptor CXCR4 on their surface. In these cells, the co-receptor CCR5 protein, which, like CXCR4, is a chemokine receptor, i s detected mainly intracellularly. We hypothesized that CD34(+) cells secre te CCR5-binding chemokines and that these factors interfere with HIV R5 int eractions with these cells, possibly by binding CCR5 or by inducing its int ernalization We found that human CD34(+) cells and CD34(+)KIT(+) cells, whi ch are enriched in myeloid progenitor cells, expressed and secreted the CCR 5 ligands RANTES, MIP-1 alpha, and MIP-1 beta and that IFN-gamma stimulated expression of these chemokines. In contrast, SDF-1, a CXCR4 ligand, was no t detectable in the CD34(+)KIT(+) cells, even by RT-PCR Conditioned media f rom CD34(+) cell culture significantly protected the T lymphocyte cell line PB-1 from infection by R5 but not X4 strains of HN. Interestingly, the sec retion of endogenous chemokines decreased with the maturation of CD34(+) ce lls, although ex vivo, expanded megakaryoblasts still secreted a significan t amount of RANTES. Synthesis of CCR5-binding chemokines by human CD34(+) c ells and megakaryoblasts therefore largely determines the susceptibility of these cells to infection by R5 HIV strains. We postulate that therapeutic agents that induce the endogenous synthesis of chemokines in human hematopo ietic cells may protect these cells from HN infection.