Human CD34(+) cells express CXCR4 and its ligand stromal cell-derived factor-1. Implications for infection by T-cell tropic human immunodeficiency virus

Human CD34(+) hematopoietic progenitor cells obtained from bone marrow (BM) , umbilical cord blood (UCB), and mobilized peripheral blood (MPB) were pur ified and investigated for the expression of the chemokine receptor CXCR4 a nd its ligand, stromal cell-derived factor-1 (SDF-1). CXCR4 was found prese nt on the cell surface of all CD34(+) cells, although it was expressed at l ower density on MPB with respect to BM CD34(+) cells. Freshly isolated and in vitro-cultured CD34(+) cells also coexpressed SDF-1 mRNA, as determined by reverse transcriptase-polymerase chain reaction (RT-PCR). Of interest, C D34(+)/CD38(+) committed progenitor cells, unlike primitive CD34(+)/CD38(-) cells, expressed SDF-1 mRNA. Supernatants from in vitro-cultured CD34(+) c ells contained substantial (3 to 8 ng/mL) amounts of SDF-1 by enzyme-linked immunosorbent assay and induced migration of CD34(+) cells. Because CD34() cells express low levels of CD4, the primary receptor of the human immuno deficiency virus (HIV), and CXCR4 is a coreceptor for T-cell tropic (X4) HI V strains, we investigated the susceptibility of CD34(+) cells to infection by this subset of viruses. Lack of productive infection was almost invaria bly observed as determined by a conventional RT activity in culture superna tants and by real-time PCR for HIV DNA in CD34(+) cells exposed to both lab oratory adapted (LAI) and primary (BON) X4 T-cell tropic HIV-1 strain, solu ble gp120 Env (sgp120) from X4 HIV-1 efficiently blocked binding of the ant i-CD4 Leu3a monoclonal antibody (MoAb) to either human CD4(+) T cells or CD 34(+) cells. In contrast, sgp120 interfered with an anti-CXCR4 MoAb binding to human T lymphocytes, but not to CD34(+) cells. However, CXCR4 on CD34() cells was downregulated by SDF-1. These results suggest that CXCR4 and it s ligand SDF-1 expressed in CD34(+) progenitors may play an important role in regulating the local and systemic trafficking of these cells. Moreover, these findings suggest multiple and potentially synergistic mechanisms at t he basis of the resistance of CD34(+) cells to X4 HIV infection, including their ability to produce SDF-1, and the lack of CXCR4 internalization follo wing gp120 binding to CD4. (C) 1999 by The American Society of Hematology.