Coreceptor chemokine receptor expression on human hematopoietic cells: Biological implications for human immunodeficiency virus-type 1 infection

The recent discovery of chemokine receptors as coreceptors for human immuno deficiency virus-type 1 (HIV-1) entry offers new avenues for investigating the pathogenesis of acquired immunodeficiency syndrome (AIDS)-related cytop enias. To this end, we sought to (1) phenotype human hematopoietic cells fo r CD4 and the HIV-1 coreceptors CXCR4, CCR5, CCR3, and CCR2b; (2) correlate CD4 and chemokine receptor expression with their susceptibility to HIV-1 i nfection; and (3) examine any potential interplay between inflammatory cyto kines released during HIV-1 infection and regulation of chemokine receptor expression. Fluorescence-activated cell sorting (FACS) analysis of bone mar row mononuclear cells (BMMNC), cells derived from serum-free expanded hemat opoietic lineages (colony-forming unit-granulocyte-macrophage [CFU-GM], col ony-forming unit-megakaryocyte [CFU-Meg], and burst-forming unit-erythroid [BFU-E]), and CD34(+) cells showed differential expression of chemokine rec eptors and GD4 with some lineage specificity. Significantly, FAGS-sorted CX CR4(+)/CD34(+) cells had the same clonogeneic potential as CXCR4(-)/CD34(+) cells. Reverse transcriptase-polymerase chain reaction (RT-PGR) analysis o f FACS-sorted human candidate stem cells (HSC; CD34(+), c-kit(+) Rho123(low )) showed the presence of CXCR4 mRNA but not GD4 mRNA. Infection studies wi th HIV-1 Env-pseudotyped luciferase reporter viruses indicated that X4 Env (CXCR4-using) pseudotypes infected megakaryocytic cells, whereas R5 Env (CC R5-using) pseudotypes did not. Similarly, R5 but not X4 Env-pseudotyped vir uses infected granulocyte-macrophage cells in a CD4/CCR5-dependent manner. Erythroid cells were resistant to R5 or X4 viral infection. Finally, we fou nd that gamma-interferon treatment upregulated CXCR4 expression on primary hematopoietic cells. In summary, the delineation of chemokine receptor expr ession on primary hematopoietic cells is a first step towards dissecting th e chemokine-chemokine receptor axes that may play a role in hematopoietic c ell proliferation and homing. Furthermore, susceptibility of hematopoietic cells to HIV-1 infection is likely to be more complicated than the mere phy sical presence of CD4 and the cognate chemokine receptor. Lastly, our resul ts suggest a potential interplay between gamma-interferon secretion and CXC R4 expression. (C) 1999 by The American Society of Hematology.